Publications by authors named "Paul A James"

166 Publications

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.

J Natl Cancer Inst 2021 Jul 28. Epub 2021 Jul 28.

Department of Molecular Medicine, University La Sapienza, Rome, Italy.

Background: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

Methods: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

Results: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

Conclusions: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.
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http://dx.doi.org/10.1093/jnci/djab147DOI Listing
July 2021

An updated quantitative model to classify missense variants in the TP53 gene: a novel multifactorial strategy.

Hum Mutat 2021 Jul 17. Epub 2021 Jul 17.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and Royal Melbourne Hospital.

Multigene panel testing has led to an increase in the number of variants of uncertain significance identified in the TP53 gene, associated with Li-Fraumeni syndrome. We previously developed a quantitative model for predicting pathogenicity of P53 missense variants based on the combination of calibrated bioinformatic information and somatic to germline ratio. Here, we extended this quantitative model for the classification of P53 predicted missense variants by adding new pieces of evidence (personal and family history parameters, loss-of-function results, population allele frequency, healthy individual status by age 60, and breast tumor pathology). We also annotated which missense variants might have an effect on splicing based on bioinformatic predictions. This updated model plus annotation led to the classification of 805 variants into a clinically relevant class, which correlated well with existing ClinVar classifications, and resolved a large number of conflicting and uncertain classifications. We propose this model as a reliable approach to TP53 germline variant classification and emphasize its use in contributing to optimise TP53-specific ACMG/AMP guidelines. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/humu.24264DOI Listing
July 2021

Case-case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer.

Hum Mutat 2021 Jul 10. Epub 2021 Jul 10.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.

Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair genes. Evidence supports the existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n = 5292) referred for diagnostic multigene cancer panel testing were annotated for presence of a pathogenic gene variant; personal history of prior, concurrent, or subsequent cancer of another type; reported family history of Lynch syndrome or EC. The Pearson χ test was used to assess differences in gene variant prevalence between case sub-groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with a prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p = 3.5 × 10 ), MSH2 (p = 3.1 × 10 ), and PMS2 (p = .02). Consistent with expectations for a breast cancer gene also predisposing to EC, the variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p = 1.7 × 10 ) and PALB2 (p = .0002). Strategic case-case analyses to address cohort ascertainment bias have provided a rationale to direct future studies of candidate hereditary EC genes.
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http://dx.doi.org/10.1002/humu.24256DOI Listing
July 2021

Metaphors and why these are important in all aspects of genetic counseling.

J Genet Couns 2021 Jul 7. Epub 2021 Jul 7.

Genomic Medicine, The Royal Melbourne Hospital, Parkville, VIC, Australia.

Metaphors appear simple but are fundamental schemata allowing expression and processing of complex emotions and information. They are so embedded in language and thinking that we are often unaware of their impact, despite the crucial role of metaphors in communication, learning and creating meaning from experiences. A deeper understanding of how to recognize and work with client-generated and counselor-generated metaphors has great potential as an addition to the genetic counseling 'tool-box'. Here, we draw on studies from related health and psychotherapy fields to discuss how working purposefully with metaphors may offer a powerful way to enhance communication within a reciprocally engaged client-counselor relationship. Metaphors present ways to explain complex genetic concepts in a personally meaningful form, to gain a deeper understanding of client's experiences and emotions, to assist processing of experiences, emotions, and concepts, and to assist client and counselor to access and reflect on subconscious emotions, self-concept, and motivations. In addition, working with metaphors has been shown to facilitate coping and action. This paper sets the scene for why and how genetic counselors can utilize client-generated and counselor-generated metaphors purposefully in all areas of practice, including enhancing the therapeutic interaction with clients, as well as in supervision, training, cultural competence, and shaping of societal attitudes toward genetics.
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http://dx.doi.org/10.1002/jgc4.1463DOI Listing
July 2021

Polygenic risk in familial breast cancer: Changing the dynamics of communicating genetic risk.

J Genet Couns 2021 Jul 5. Epub 2021 Jul 5.

Psychosocial Research Group, Prince of Wales Clinical School, University of New South Wales, Sydney, NSW, Australia.

Hereditary breast cancer is associated with known genetic changes: either variants that affect function in a few rare genes or an ever-increasing number of common genomic risk variants, which combine to produce a cumulative effect, known as a polygenic risk (PR) score. While the clinical validity and utility of PR scores are still being determined, the communication of PR is a new challenge for genetic health professionals. This study investigated how PR scores are discussed in the familial cancer clinic compared with a previous study assessing the communication of monogenic risk (MR) for breast cancer. Sixty-five PR consultations between genetic health professionals and women at familial risk of breast cancer were audiotaped, transcribed, and coded using a methodology adapted from the MR study. Analysis of consultations shows that while there were similarities in communicating MR and PR, the complexity and novelty of the polygenic information influenced the style of counseling used by genetic health professionals toward a teaching model of genetic counseling, rather than a patient-centered approach. In particular, compared to MR consultations, in PR consultations significantly fewer counselees (a) were asked about their reasons for attending genetic counseling; or (b) had their information preferences, decision-making style, medical knowledge, understanding, or concerns checked. In conclusion, it is anticipated that PR scores will become part of standard clinical practice. Thus, it will be important for all genetic health professionals to be appropriately educated so that they can tailor their communication to meet patient needs.
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http://dx.doi.org/10.1002/jgc4.1458DOI Listing
July 2021

Evaluation of two population screening programmes for founder mutations in the Australian Jewish community: a protocol paper.

BMJ Open 2021 06 25;11(6):e041186. Epub 2021 Jun 25.

Hereditary Cancer Centre, Prince of Wales Hospital Cancer Services, Randwick, New South Wales, Australia.

Introduction: People of Ashkenazi Jewish (AJ) ancestry are more likely than unselected populations to have a pathogenic variant, which cause a significantly increased risk of breast, ovarian and prostate cancer. Three specific pathogenic variants, referred to as -Jewish founder mutations (B-JFM), account for >90% of pathogenic variants in people of AJ ancestry. Current practice of identifying eligible individuals for testing based on personal and/or family history has been shown to miss at least 50% of people who have one of these variants. Here we describe the protocol of the JeneScreen study-a study established to develop and evaluate two different population-based B-JFM screening programmes, offered to people of Jewish ancestry in Sydney and Melbourne, Australia.

Methods And Analysis: To rmeasure the acceptability of population-based B-JFM screening in Australia, two screening programmes using different methodologies have been developed. The Sydney JeneScreen programme provides information and obtains informed consent by way of an online tool. The Melbourne JeneScreen programme does this by way of community sessions attended in person. Participants complete questionnaires to measure clinical and psychosocial outcomes at baseline, and for those who have testing, 2 weeks postresult. Participants who decline testing are sent a questionnaire regarding reasons for declining. Participants with a B-JFM are sent questionnaires 12-month and 24-month post-testing. The questionnaires incorporate validated scales, which measure anxiety, decisional conflict and regret, and test-related distress and positive experiences, and other items specifically developed or adapted for the study. These measures will be assessed for each programme and the two population-based B-JFM screening methods will be compared.

Ethics And Dissemination: Institutional Human Research Ethics Committee approval was obtained from the South Eastern Area Health Service Human Research Ethics Committee: HREC Ref 16/125.Following the analysis of the study results, the findings will be disseminated widely through conferences and publications, and directly to participants in writing.
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http://dx.doi.org/10.1136/bmjopen-2020-041186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8237737PMC
June 2021

Genetic variants associated with inherited cardiovascular disorders among 13,131 asymptomatic older adults of European descent.

NPJ Genom Med 2021 Jun 16;6(1):51. Epub 2021 Jun 16.

Department of Epidemiology and Preventive Medicine, School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.

Genetic testing is used to optimise the management of inherited cardiovascular disorders that can cause sudden cardiac death. Yet more genotype-phenotype correlation studies from populations not ascertained on clinical symptoms or family history of disease are required to improve understanding of gene penetrance. We performed targeted sequencing of 25 genes used routinely in clinical genetic testing for inherited cardiovascular disorders in a population of 13,131 asymptomatic older individuals (mean age 75 years) enrolled in the ASPREE trial. Participants had no prior history of cardiovascular disease events, dementia or physical disability at enrolment. Variants were classified following ACMG/AMP standards. Sudden and rapid cardiac deaths were clinically adjudicated as ASPREE trial endpoints, and assessed during mean 4.7 years of follow-up. In total, 119 participants had pathogenic/deleterious variants in one of the 25 genes analysed (carrier rate of 1 in 110 or 0.9%). Participants carried variants associated with hypertrophic cardiomyopathy (N = 24), dilated cardiomyopathy (N = 29), arrhythmogenic right-ventricular cardiomyopathy (N = 22), catecholaminergic polymorphic ventricular tachycardia (N = 4), aortopathies (N = 1), and long-QT syndrome (N = 39). Among 119 carriers, two died from presumed sudden/rapid cardiac deaths during follow-up (1.7%); both with pathogenic variants in long-QT syndrome genes (KCNQ1, SCN5A). Among non-carriers, the rate of sudden/rapid cardiac deaths was significantly lower (0.08%, 11/12936, p < 0.001). Variants associated with inherited cardiovascular disorders are found in asymptomatic individuals aged 70 years and older without a history of cardiovascular disease.
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http://dx.doi.org/10.1038/s41525-021-00211-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209162PMC
June 2021

Investigation of monogenic causes of familial breast cancer: data from the BEACCON case-control study.

NPJ Breast Cancer 2021 Jun 11;7(1):76. Epub 2021 Jun 11.

Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.

Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2, including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon-intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM, PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN. An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10) and missense (OR 1.27, p = 3.96 × 10) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2-4 and individually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1, WRN, PARP2, CTH and CDK9. The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.
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http://dx.doi.org/10.1038/s41523-021-00279-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8196173PMC
June 2021

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Genet Med 2021 Jun 10. Epub 2021 Jun 10.

Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Purpose: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS and CBC risk.

Results: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.
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http://dx.doi.org/10.1038/s41436-021-01198-7DOI Listing
June 2021

Genetic Dominant Variants in Segregating in Families with SCA48, Display In Vitro Functional Impairments Indistinctive from Recessive Variants Associated with SCAR16.

Int J Mol Sci 2021 May 30;22(11). Epub 2021 May 30.

Department of Medical Genetics, Haukeland University Hospital, 5021 Bergen, Norway.

Variants in cause both autosomal recessive (SCAR16) and dominant (SCA48) spinocerebellar ataxia. Reports from 18 variants causing SCA48 show that the clinical picture includes later-onset ataxia with a cerebellar cognitive affective syndrome and varying clinical overlap with SCAR16. However, little is known about the molecular properties of dominant variants. Here, we describe three SCA48 families with novel, dominantly inherited variants (p.Arg51_Ile53delinsProAla, p.Lys143_Trp147del, and p.Gly249Val). All the patients developed symptoms from 30 years of age or later, all had cerebellar atrophy, and 4 had cognitive/psychiatric phenotypes. Investigation of the structural and functional consequences of the recombinant C-terminus of HSC70-interacting protein (CHIP) variants was performed in vitro using ubiquitin ligase activity assay, circular dichroism assay and native polyacrylamide gel electrophoresis. These studies revealed that dominantly and recessively inherited variants showed similar biochemical defects, including impaired ubiquitin ligase activity and altered oligomerization properties of the CHIP. Our findings expand the molecular understanding of SCA48 but also mean that assumptions concerning unaffected carriers of recessive variants in SCAR16 families must be re-evaluated. More investigations are needed to verify the disease status of SCAR16 heterozygotes and elucidate the molecular relationship between SCA48 and SCAR16 diseases.
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http://dx.doi.org/10.3390/ijms22115870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199271PMC
May 2021

Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.

NPJ Breast Cancer 2021 May 12;7(1):52. Epub 2021 May 12.

School of Biomedical Sciences and Pharmacy, University of Newcastle, Callaghan, NSW, Australia.

Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82-1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09-1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
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http://dx.doi.org/10.1038/s41523-021-00255-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115524PMC
May 2021

Oncologists' perspectives of telephone genetic counseling to facilitate germline BRCA1/2 testing for their patients with high-grade serous ovarian cancer.

J Community Genet 2021 Jul 6;12(3):449-457. Epub 2021 May 6.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, 3000, Australia.

Poly ADP ribose polymerase (PARP) inhibitors offer a survival advantage to women with high-grade serous ovarian cancer who have a germline BRCA1/2 pathogenic variant (PV). Yet, rates of genetic testing among this population have remained persistently low. A national, centralized telephone genetic counseling service was established in January 2016 in Australia to improve access to genetic services and facilitate BRCA1/2 testing for this population to inform treatment. Medical oncologists can refer their patients with high-grade serous ovarian cancer to this service for genetic testing. This study aimed to explore oncologists' experiences of using this telephone genetic counseling service for their patients with high-grade serous ovarian cancer. A qualitative approach using semi-structured telephone interviews was undertaken with Australian oncologists who had referred patients to the telephone genetic counseling service. Sixteen oncologists participated and described referring patients to the telephone genetic counseling service due to the timeliness of obtaining a genetic counseling appointment and BRCA1/2 test results. They also reported this service offered convenience for patients living in regional or rural areas who then did not have to travel for an appointment with a clinical genetics service. Many oncologists noted the importance of in-person genetic counseling for patients who received positive BRCA1/2 results. Areas for improvement identified by the oncologists related to communication issues between the service and the patient. Overall, findings suggest that oncologists perceived telephone genetic counseling as an acceptable and useful healthcare service for patients with high-grade serous ovarian cancer. Moreover, they perceived telephone genetic counseling to be efficient, delivering convenient genetic counseling to patients.
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http://dx.doi.org/10.1007/s12687-021-00530-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8241936PMC
July 2021

Genetic testing in dementia-A medical genetics perspective.

Int J Geriatr Psychiatry 2021 Aug 28;36(8):1158-1170. Epub 2021 Mar 28.

Department of Genomic Medicine, The Royal Melbourne Hospital, Parkville, Victoria, Australia.

Objective: When a genetic cause is suspected in a person with dementia, it creates unique diagnostic and management challenges to the treating clinician. Many clinicians may be unaware of the practicalities surrounding genetic testing for their patients, such as when to test and what tests to use and how to counsel patients and their families. This review was conducted to provide guidance to clinicians caring for patients with dementia regarding clinically relevant genetics.

Methods: We searched PubMed for studies that involved genetics of dementia up to March 2020. Patient file reviews were also conducted to create composite cases.

Results: In addition to families where a strong Mendelian pattern of family history is seen, people with younger age of onset, especially before the age of 65 years were found to be at an increased risk of harbouring a genetic cause for their dementia. This review discusses some of the most common genetic syndromes, including Alzheimer disease, frontotemporal dementia, vascular dementia, Parkinson disease dementia/dementia with Lewy bodies and some rarer types of genetic dementias, along with illustrative clinical case studies. This is followed by a brief review of the current genetic technologies and a discussion on the unique genetic counselling issues in dementia.

Conclusions: Inclusion of genetic testing in the diagnostic pathway in some patients with dementia could potentially reduce the time taken to diagnose the cause of their dementia. Although a definite advantage as an addition to the diagnostic repository, genetic testing has many pros and cons which need to be carefully considered first.
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http://dx.doi.org/10.1002/gps.5535DOI Listing
August 2021

Mainstream genetic testing for breast cancer patients: early experiences from the Parkville Familial Cancer Centre.

Eur J Hum Genet 2021 May 15;29(5):872-880. Epub 2021 Mar 15.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Parkville, VIC, Australia.

The demand for genetic testing of hereditary breast cancer genes such as BRCA1 and BRCA2 has continued to increase with the lowering costs of testing, raised awareness in the general public, and implications for breast cancer treatment when a patient is identified as having a germline pathogenic variant. Historically within Australia, patients affected by high genetic risk breast cancers have been referred to a familial cancer centre (FCC) for assessment and testing, resulting in wait times for an appointment for pre- and post-test genetic counselling and an increased demand on the public-funded FCC. To improve patient access and pace of genetic testing, as well as refocus FCC resources, a mainstream clinical genetic testing program was rolled out in September 2017 through the Parkville FCC (PFCC) in Australia at 10 hospital sites. This program enables specialist doctors of eligible patients affected by breast cancer to arrange genetic testing directly at an oncology/surgical appointment and follow up the results as part of the patients' routine clinical care. In this model, the specialist doctor is responsible for any treatment implications of the genetic test result, and the PFCC is responsible for result interpretation, future cancer risk, family cascade testing and segregation testing where warranted. To date the program has had successful uptake, a notable pathogenic variant detection rate, reduced the burden on the PFCC enabling a reallocation of resources and has streamlined the process of genetic testing for eligible patients. Investigation into the patient and clinician experiences of the mainstream program is required.
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http://dx.doi.org/10.1038/s41431-021-00848-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111023PMC
May 2021

Communicating polygenic risk scores in the familial breast cancer clinic.

Patient Educ Couns 2021 Mar 1. Epub 2021 Mar 1.

Psychosocial Research Group, Prince of Wales Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2052, Australia; The University of Queensland Diamantina Institute, Dermatology Research Centre, The University of Queensland, Brisbane, QLD, Australia. Electronic address:

Objective: To describe the communication of polygenic risk scores (PRS) in the familial breast cancer setting.

Methods: Consultations between genetic healthcare providers (GHP) and female patients who received their PRS for breast cancer risk were recorded (n = 65). GHPs included genetic counselors (n = 8) and medical practitioners (n = 5) (i.e. clinical geneticists and oncologists). A content analysis was conducted and logistic regression was used to assess differences in communication behaviors between genetic counselors (n = 8) and medical practitioners (n = 5).

Results: Of the 65 patients, 31 (47.7 %) had a personal history of breast cancer, 18 of whom received an increased PRS (relative risk >1.2). 25/34 unaffected patients received an increased PRS. Consultations were primarily clinician-driven and focused on biomedical information. There was little difference between the biomedical information provided by genetic counselors and medical practitioners. However, genetic counselors were significantly more likely to utilize strategies to build patient rapport and counseling techniques.

Conclusions: Our findings provide one of the earliest reports on how breast cancer PRSs are communicated to women.

Practice Implications: Key messages for communicating PRSs were identified, namely: discussing differences between polygenic and monogenic testing, the multifactorial nature of breast cancer risk, polygenic inheritance and current limitation of PRSs.
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http://dx.doi.org/10.1016/j.pec.2021.02.046DOI Listing
March 2021

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers.

Nat Commun 2021 02 17;12(1):1078. Epub 2021 Feb 17.

Copenhagen General Population Study, Herlev and Gentofte Hospital Copenhagen University Hospital, Herlev, Denmark.

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers.
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http://dx.doi.org/10.1038/s41467-020-20496-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890067PMC
February 2021

Clinical and laboratory reporting impact of ACMG-AMP and modified ClinGen variant classification frameworks in MYH7-related cardiomyopathy.

Genet Med 2021 06 10;23(6):1108-1115. Epub 2021 Feb 10.

Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Parkville, VIC, Australia.

Purpose: ClinGen provides gene-specific guidance for interpretation of sequence variants in MYH7. We assessed laboratory and clinical impact of reclassification by the American College of Medical Genetics and Genomics-Association for Molecular Pathology (ACMG-AMP) and ClinGen recommendations in 43 MYH7 variants reported by a diagnostic laboratory between 2013 and 2017.

Methods: Fifty-two proband reports containing MYH7 variants were reinterpreted by original ACMG-AMP and ClinGen guidelines. Evidence items were compared across schemes and reasons for classification differences recorded. Laboratory impact was assessed by number of recommended report reissues, and reclassifications coded as clinically "actionable" or "equivalent." Available pedigrees were reviewed to describe projected cascade impact.

Results: ClinGen produced a higher proportion of diagnostic classifications (65% of variants) compared with ACMG-AMP (54%) and fewer variants of uncertain significance (30% versus 42%). ClinGen classification resulted in actionable changes in 18% of variants with equal upgrades and downgrades from original report. ClinGen's revisions to PM1 and PS4 contributed to classification differences in 21% and 19% of variants respectively. Each classification change per proband report impacted, on average, 3.1 cascade reports with a further 6.3 first- and second-degree relatives potentially available for genotyping per family.

Conclusion: ClinGen's gene-specific criteria provide expert-informed guidance for interpretation of MYH7 sequence variants. Periodic re-evaluation improves diagnostic confidence and should be considered by clinical and laboratory teams.
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http://dx.doi.org/10.1038/s41436-021-01107-yDOI Listing
June 2021

Influence of lived experience on risk perception among women who received a breast cancer polygenic risk score: 'Another piece of the pie'.

J Genet Couns 2021 Jun 19;30(3):849-860. Epub 2021 Jan 19.

The Kinghorn Cancer Centre and Cancer Division, Garvan Institute of Medical Research, Darlinghurst, Australia.

Polygenic risk scores (PRS) are personalized assessments of disease risk based on the cumulative effect of common low-risk genetic variants. PRS have been shown to accurately predict women's breast cancer risk and are likely to be incorporated into personalized breast cancer risk management programs. However, there are few studies investigating the individual impact of receiving a breast cancer PRS. Existing studies have not demonstrated significant changes in perceived risk or risk management behaviors after receipt of polygenic risk information. The aim of this qualitative study was to explore how women with a family history of breast cancer construct breast cancer risk perceptions after receipt of a breast cancer PRS. Unaffected women with a family history of breast cancer who had not previously received genetic counseling regarding their breast cancer risk were invited to participate in this study. In-depth, semi-structured interviews were conducted with 20 women who attended a familial cancer clinic in the Australian states of Victoria and Tasmania. Data were analyzed using an inductive thematic approach. Women's lived experience played a significant role in the construction and maintenance of their breast cancer risk perception. Women's pre-existing risk perceptions were informed by their family history and their knowledge that breast cancer is a multifactorial disease. Knowing that breast cancer is a multifactorial disease enabled most women to integrate genetic information with their pre-existing notions of risk. Women reported that the information they received was consistent with their existing notions of personal risk and screening advice. Therefore, the PRS did not lead to a change in perceived risk or risk management behaviors for most women. The results of this study provide insight into how polygenic risk information is integrated with pre-existing notions of risk, which will inform its implementation into clinical practice.
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http://dx.doi.org/10.1002/jgc4.1384DOI Listing
June 2021

The clinical utility of exome sequencing and extended bioinformatic analyses in adolescents and adults with a broad range of neurological phenotypes: an Australian perspective.

J Neurol Sci 2021 01 3;420:117260. Epub 2020 Dec 3.

Health Economics Unit, Centre for Health Policy, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia; Australian Genomics Health Alliance, Melbourne, Australia.

Currently there is no secured ongoing funding in Australia for next generation sequencing (NGS) such as exome sequencing (ES) for adult neurological disorders. Studies have focused on paediatric populations in research or highly specialised settings, utilised standard NGS pipelines focusing only on small insertions, deletions and single nucleotide variants, and not explored impacts on management in detail. This prospective multi-site study performed ES and an extended bioinformatics repeat expansion analysis pipeline, on patients with broad phenotypes (ataxia, dementia, dystonia, spastic paraparesis, motor neuron disease, Parkinson's disease and complex/not-otherwise-specified), with symptom onset between 2 and 60 years. Genomic data analysis was phenotype-driven, using virtual gene panels, reported according to American College of Medical Genetics and Genomics guidelines. One-hundred-and-sixty patients (51% female) were included, median age 52 years (range 14-79) and median 9 years of symptoms. 34/160 (21%) patients received a genetic diagnosis. Highest diagnostic rates were in spastic paraparesis (10/25, 40%), complex/not-otherwise-specified (10/38, 26%) and ataxia (7/28, 25%) groups. Findings were considered 'possible/uncertain' in 21/160 patients. Repeat expansion detection identified an unexpected diagnosis of Huntington disease in an ataxic patient with negative ES. Impacts on management, such as more precise and tailored care, were seen in most diagnosed patients (23/34, 68%). ES and a novel bioinformatics analysis pipepline had a substantial diagnostic yield (21%) and management impacts for most diagnosed patients, in heterogeneous, complex, mainly adult-onset neurological disorders in real-world settings in Australia, providing evidence for NGS and complementary multiple, new technologies as valuable diagnostic tools.
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http://dx.doi.org/10.1016/j.jns.2020.117260DOI Listing
January 2021

Specifications of the ACMG/AMP variant interpretation guidelines for germline TP53 variants.

Hum Mutat 2021 Mar 25;42(3):223-236. Epub 2020 Dec 25.

Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, USA.

Germline pathogenic variants in TP53 are associated with Li-Fraumeni syndrome, a cancer predisposition disorder inherited in an autosomal dominant pattern associated with a high risk of malignancy, including early-onset breast cancers, sarcomas, adrenocortical carcinomas, and brain tumors. Intense cancer surveillance for individuals with TP53 germline pathogenic variants is associated with reduced cancer-related mortality. Accurate and consistent classification of germline variants across clinical and research laboratories is important to ensure appropriate cancer surveillance recommendations. Here, we describe the work performed by the Clinical Genome Resource TP53 Variant Curation Expert Panel (ClinGen TP53 VCEP) focused on specifying the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification to the TP53 gene. Specifications were developed for 20 ACMG/AMP criteria, while nine were deemed not applicable. The original strength level for the 10 criteria was also adjusted due to current evidence. Use of TP53-specific guidelines and sharing of clinical data among experts and clinical laboratories led to a decrease in variants of uncertain significance from 28% to 12% compared with the original guidelines. The ClinGen TP53 VCEP recommends the use of these TP53-specific ACMG/AMP guidelines as the standard strategy for TP53 germline variant classification.
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http://dx.doi.org/10.1002/humu.24152DOI Listing
March 2021

Implementing gene curation for hereditary cancer susceptibility in Australia: achieving consensus on genes with clinical utility.

J Med Genet 2020 Nov 9. Epub 2020 Nov 9.

Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia

Background: The strength of evidence supporting the validity of gene-disease relationships is variable. Hereditary cancer has the additional complexity of low or moderate penetrance for some confirmed disease-associated alleles.

Methods: To promote national consistency in interpretation of hereditary cancer/tumour gene test results, we requested opinions of representatives from Australian Family Cancer Clinics regarding the clinical utility of 157 genes initially collated for a national research project. Viewpoints were sought by initial survey, face-to-face workshop and follow-up survey. Subsequent review was undertaken by the eviQ Cancer Genetics Reference Committee, a national resource providing evidence-based and consensus-driven cancer treatment protocols.

Results: Genes were categorised by clinical actionability as: relevant for testing on presentation of common cancer/tumour types (n=45); relevant for testing in the context of specific rare phenotypes (n=74); insufficient clinical utility (n=34) or contentious clinical utility (n=3). Opinions for several genes altered during the study time frame, due to new information.

Conclusion: Through an iterative process, consensus was achieved on genes with clinical utility for hereditary cancer/tumour conditions in the Australian setting. This study highlighted need for regular review of gene-disease lists, a role assumed in Australia for hereditary cancer/tumour predisposition genes by the eviQ Cancer Genetics Reference Committee.
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http://dx.doi.org/10.1136/jmedgenet-2020-107140DOI Listing
November 2020

Finding the five-year window: A qualitative study examining young women's decision-making and experience of using tamoxifen to reduce BRCA1/2 breast cancer risk.

Psychooncology 2021 02 11;30(2):159-166. Epub 2020 Oct 11.

Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

Objective: Tamoxifen has been demonstrated to reduce breast cancer risk in high-risk, premenopausal women. Yet, very few young women with hereditary breast and ovarian cancer syndrome in Australia use tamoxifen, despite this being a less-invasive option compared to risk-reducing mastectomy. This study aims to examine young women's decision-making about and experience of taking tamoxifen to reduce their breast cancer risk.

Methods: Young women with a BRCA1/2 mutation participated in semi-structured qualitative interviews, recruited mainly from a metropolitan clinical genetics service. Data were analysed using an inductive, team-based approach to thematic analysis.

Results: Forty interviews with women aged 20-40 years with a BRCA1/2 mutation were conducted. Eleven women could not recall discussing tamoxifen with their healthcare provider or were too young to commence cancer risk management. Twenty-three women chose not to use tamoxifen because it is contraindicated for pregnancy or because it did not offer immediate and great enough risk reduction compared to bilateral risk-reducing mastectomy. Six women who were definite about not wanting to have children during the following 5-year period chose to use tamoxifen, and most experienced none or transient side effects.

Conclusions: Decision-making about tamoxifen was nuanced and informed by considerations characteristic of young adulthood, especially childbearing. Therefore, clinical discussions about tamoxifen with young women with a BRCA1/2 mutation must include consideration of their reproductive plans.
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http://dx.doi.org/10.1002/pon.5556DOI Listing
February 2021

Genotype-phenotype correlations among TP53 carriers: Literature review and analysis of probands undergoing multi-gene panel testing and single-gene testing.

Cancer Genet 2020 10 11;248-249:11-17. Epub 2020 Sep 11.

QIMR Berghofer Medical Research Institute, Genetics and Computational Division, 300 Herston Rd, Herston, QLD 4006, Australia. Electronic address:

Pathogenic germline variants in the TP53 gene predispose to a wide range of cancers, known collectively as Li-Fraumeni syndrome (LFS). There has been much research aimed to identify genotype-phenotype correlations, that is, differences between variant location and/or effect and cancer spectrum. These correlations, should they exist, have potential to impact clinical management of carriers. Review of previously published studies showed a variety of study designs and inconsistency in reported findings. Here, we used pooled data from 427 TP53 carriers who had undergone multigene panel testing and 154 TP53 carriers identified by single-gene testing to investigate correlations between TP53 genotype (truncating variants, hotspot variants, other missense variants with dominant-negative effect, missense variants without dominant-negative effect) and a number of LFS-selected malignancies. Our results suggest that carriers of truncating and hotspot variants might be more likely to present with LFS cancers and have shorter time to first cancer diagnosis compared to carriers of other variant types. However, the differences observed were minor, and we conclude that there is currently insufficient evidence to consider location and/or molecular effect of pathogenic variants to assist with clinical management of TP53 carriers. Larger studies are necessary to confirm the correlations suggested by our analysis.
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http://dx.doi.org/10.1016/j.cancergen.2020.09.002DOI Listing
October 2020

The Challenge of External Validity: Why Specialties Interpret Evidence Differently.

Fam Med 2020 09;52(8):548-550

Department of Health Services Research, Management and Policy, University of Florida.

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http://dx.doi.org/10.22454/FamMed.2020.476348DOI Listing
September 2020

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Genet Med 2020 10 15;22(10):1653-1666. Epub 2020 Jul 15.

Royal Devon & Exeter Hospital, Department of Clinical Genetics, Exeter, UK.

Purpose: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10) carriers. The associations in the prospective cohort were similar.

Conclusion: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.
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http://dx.doi.org/10.1038/s41436-020-0862-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521995PMC
October 2020

Characterization of the Cancer Spectrum in Men With Germline BRCA1 and BRCA2 Pathogenic Variants: Results From the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA).

JAMA Oncol 2020 08;6(8):1218-1230

Department of Oncology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

Importance: The limited data on cancer phenotypes in men with germline BRCA1 and BRCA2 pathogenic variants (PVs) have hampered the development of evidence-based recommendations for early cancer detection and risk reduction in this population.

Objective: To compare the cancer spectrum and frequencies between male BRCA1 and BRCA2 PV carriers.

Design, Setting, And Participants: Retrospective cohort study of 6902 men, including 3651 BRCA1 and 3251 BRCA2 PV carriers, older than 18 years recruited from cancer genetics clinics from 1966 to 2017 by 53 study groups in 33 countries worldwide collaborating through the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Clinical data and pathologic characteristics were collected.

Main Outcomes And Measures: BRCA1/2 status was the outcome in a logistic regression, and cancer diagnoses were the independent predictors. All odds ratios (ORs) were adjusted for age, country of origin, and calendar year of the first interview.

Results: Among the 6902 men in the study (median [range] age, 51.6 [18-100] years), 1634 cancers were diagnosed in 1376 men (19.9%), the majority (922 of 1,376 [67%]) being BRCA2 PV carriers. Being affected by any cancer was associated with a higher probability of being a BRCA2, rather than a BRCA1, PV carrier (OR, 3.23; 95% CI, 2.81-3.70; P < .001), as well as developing 2 (OR, 7.97; 95% CI, 5.47-11.60; P < .001) and 3 (OR, 19.60; 95% CI, 4.64-82.89; P < .001) primary tumors. A higher frequency of breast (OR, 5.47; 95% CI, 4.06-7.37; P < .001) and prostate (OR, 1.39; 95% CI, 1.09-1.78; P = .008) cancers was associated with a higher probability of being a BRCA2 PV carrier. Among cancers other than breast and prostate, pancreatic cancer was associated with a higher probability (OR, 3.00; 95% CI, 1.55-5.81; P = .001) and colorectal cancer with a lower probability (OR, 0.47; 95% CI, 0.29-0.78; P = .003) of being a BRCA2 PV carrier.

Conclusions And Relevance: Significant differences in the cancer spectrum were observed in male BRCA2, compared with BRCA1, PV carriers. These data may inform future recommendations for surveillance of BRCA1/2-associated cancers and guide future prospective studies for estimating cancer risks in men with BRCA1/2 PVs.
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http://dx.doi.org/10.1001/jamaoncol.2020.2134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7333177PMC
August 2020

Medically actionable pathogenic variants in a population of 13,131 healthy elderly individuals.

Genet Med 2020 11 1;22(11):1883-1886. Epub 2020 Jul 1.

Department of Genetics and Genomic Sciences, Icahn Institute for Data Science and Genomic Technology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Purpose: To measure the prevalence of medically actionable pathogenic variants (PVs) among a population of healthy elderly individuals.

Methods: We used targeted sequencing to detect pathogenic or likely pathogenic variants in 55 genes associated with autosomal dominant medically actionable conditions, among a population of 13,131 individuals aged 70 or older (mean age 75 years) enrolled in the ASPirin in Reducing Events in the Elderly (ASPREE) trial. Participants had no previous diagnosis or current symptoms of cardiovascular disease, physical disability or dementia, and no current diagnosis of life-threatening cancer. Variant curation followed American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) standards.

Results: One in 75 (1.3%) healthy elderly individuals carried a PV. This was lower than rates reported from population-based studies, which have ranged from 1.8% to 3.4%. We detected 20 PV carriers for Lynch syndrome (MSH6/MLH1/MSH2/PMS2) and 13 for familial hypercholesterolemia (LDLR/APOB/PCSK9). Among 7056 female participants, we detected 15 BRCA1/BRCA2 PV carriers (1 in 470 females). We detected 86 carriers of PVs in lower-penetrance genes associated with inherited cardiac disorders.

Conclusion: Medically actionable PVs are carried in a healthy elderly population. Our findings raise questions about the actionability of lower-penetrance genes, especially when PVs are detected in the absence of symptoms and/or family history of disease.
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http://dx.doi.org/10.1038/s41436-020-0881-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606791PMC
November 2020

Suggested application of HER2+ breast tumor phenotype for germline TP53 variant classification within ACMG/AMP guidelines.

Hum Mutat 2020 09 12;41(9):1555-1562. Epub 2020 Jun 12.

Genetics and Computational Division, QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia.

Early onset breast cancer is the most common malignancy in women with Li-Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of noncarriers, but this information has not been incorporated into variant interpretation models for TP53. Breast tumor pathology is already being used quantitatively for assessing pathogenicity of germline variants in other genes, and it has been suggested that this type of evidence can be incorporated into current American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines for germline variant classification. Here, by reviewing published data and using internal datasets separated by different age groups, we investigated if breast tumor HER2+ status has utility as a predictor of TP53 germline variant pathogenicity, considering age at diagnosis. Overall, our results showed that the identification of HER2+ breast tumors diagnosed before the age of 40 can be conservatively incorporated into the current TP53-specific ACMG/AMP PP4 criterion, following a point system detailed in this manuscript. Further larger studies will be needed to reassess the value of HER2+ breast tumors diagnosed at a later age.
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http://dx.doi.org/10.1002/humu.24060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484289PMC
September 2020

Expanding the clinical and genetic spectrum of ALPK3 variants: Phenotypes identified in pediatric cardiomyopathy patients and adults with heterozygous variants.

Am Heart J 2020 07 21;225:108-119. Epub 2020 Apr 21.

Bruce Lefroy Centre for Genetic Health Research, Murdoch Children's Research Institute, Victoria, Australia; Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Victoria, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Victoria, Australia.

Introduction: Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.

Methods And Results: We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults. Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%-3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-16.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6×10; U.S. cohort, P = 2.2×10).

Conclusion: Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy.
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http://dx.doi.org/10.1016/j.ahj.2020.03.023DOI Listing
July 2020
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