ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.824G>A (p.Gly275Asp) (rs397509327)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000490300 SCV001161575 benign Breast-ovarian cancer, familial 1 2019-06-18 reviewed by expert panel curation Variant allele has low bioinformatic likelihood to encode a missense alteration affecting protein function (Missense prior probability 0.02; http://priors.hci.utah.edu/PRIORS/), AND low bioinformatic likelihood to alter mRNA splicing (splicing prior 0.02; http://priors.hci.utah.edu/PRIORS/), AND minor allele frequency 0.00104 (East Asian), derived from gnomAD v2.1.1 non-cancer (2019-05-13).
Invitae RCV000589691 SCV000077172 likely benign not provided 2019-02-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130114 SCV000184944 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000120298 SCV000210091 likely benign not specified 2017-07-10 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240746 SCV000265882 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Soonchunhyang University Bucheon Hospital,Soonchunhyang University Medical Center RCV000490300 SCV000267229 uncertain significance Breast-ovarian cancer, familial 1 2016-03-18 criteria provided, single submitter reference population
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000589691 SCV000337720 uncertain significance not provided 2015-11-24 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000120298 SCV000538457 uncertain significance not specified 2016-12-20 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been reported in 4 papers in HGMD, that include affected and unaffected individuals. This variant is classified in ClinVar with 2 stars as VUS by Invitae, Ambry, GeneDx, and West China Hospital. The variant has a Max MAF of 0.13% in ExAC (12 East Asian alleles) and 0.1% in gnomAD (20 alleles). 19 non-mammals have an Asp at this position.
Integrated Genetics/Laboratory Corporation of America RCV000120298 SCV000699315 likely benign not specified 2019-05-24 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.824G>A (p.Gly275Asp) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00022 in 298510 control chromosomes, exclusively reported within the East Asian subpopulation at a frequency of 0.001 (in the gnomAD database and in Momozawa_2018). This frequency is comparable to the expected maximum frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (0.001 vs 0.001), suggesting the variant could be a benign polymorphism found in populations from East Asia. In addition, the variant was reported in some East Asian subpopulations with even higher allele frequencies, e.g. in Koreans (0.0026, in gnomAD), and in Japanese (0.0012, in HGVD), further supporting a benign role for the variant. The c.824G>A variant has been reported in the literature numerous individuals (generally in East Asians) affected with breast- and ovarian cancer and other tumor phenotypes (Carney_2010, Haffty_2009, Judkins_2005, Kato_2016, Kawahara_2004, Sakayori_2003, Shin_2016, Suter_2004, Zhong_2016, Bhaskaran_2019, Chan_2018, Choi_2018, Lee_2018, Park_2017), but was also found in several unaffected East Asian controls (Park_2017, Momozawa_2018). A co-occurrence with another likely pathogenic variant has been reported (BRCA1 c.5165C>T, p.Ser1722Phe; Chan_2018), providing supporting evidence for a benign role. Two recent case-control association studies, involving breast cancer patients and controls of Korean- (Park_2017) and Japanese ancestry (Momozawa 2018), found that the variant is not associated with a significant increase in breast/ovarian cancer risk, and therefore the authors of these studies classified that the variant as likely benign/benign, respectively. In addition, in a study involving Korean breast cancer patients, multifactorial probability was estimated by performing systematic assessments of variants of unknown significance in the BRCA genes (which included analysis of co-occurrence with known deleterious mutations, personal and family history of cancer and tumor pathology) and predicted this variant to be likely benign (Lee_2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as likely benign (3x) and VUS (5x). Based on the evidence outlined above, the variant was classified as likely benign.
Color RCV000130114 SCV000910845 likely benign Hereditary cancer-predisposing syndrome 2015-11-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589691 SCV001133654 likely benign not provided 2018-08-28 criteria provided, single submitter clinical testing
Mendelics RCV000490300 SCV001140618 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000120298 SCV000084450 not provided not specified 2013-09-19 no assertion provided reference population

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