ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.811G>A (p.Val271Met)

gnomAD frequency: 0.00003  dbSNP: rs80357244
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Total submissions: 21
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195348 SCV000077166 benign Hereditary breast ovarian cancer syndrome 2024-02-01 criteria provided, single submitter clinical testing
GeneDx RCV000049153 SCV000209916 likely benign not specified 2018-01-25 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.
CSER _CC_NCGL, University of Washington RCV000195348 SCV000212208 likely benign Hereditary breast ovarian cancer syndrome 2015-03-11 criteria provided, single submitter research
Ambry Genetics RCV000162818 SCV000213301 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000112794 SCV000785269 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2017-06-23 criteria provided, single submitter clinical testing
Mendelics RCV000195348 SCV000839293 benign Hereditary breast ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000049153 SCV000887736 benign not specified 2022-01-21 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000162818 SCV000903508 likely benign Hereditary cancer-predisposing syndrome 2016-10-13 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000049153 SCV000918672 benign not specified 2021-12-02 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.811G>A (p.Val271Met) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 316878 control chromosomes, predominantly at a frequency of 0.0013 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.3 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.811G>A has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (example: Judkins_2005, Kim_2006, Han_2006, Yoshikawa_1999, Katagiri_1996, Chao_2016, Fernandes_2016, Ryu_2017, Chan_2018, Momozawa_2018, Ohmoto_2018, Emi_1998, Hirotsu_2015, Kim_2021, Nakagomi_2018), however these data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function (Yoshikawa_1999, Starita_2015). These results showed no damaging effect of this variant (Starita_2015). Twelve ClinVar submitters have assessed this variant after 2014: one classified it as a variant of uncertain significance, eight as likely benign, and 3 as benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000112794 SCV001140620 benign Breast-ovarian cancer, familial, susceptibility to, 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000112794 SCV001280987 likely benign Breast-ovarian cancer, familial, susceptibility to, 1 2017-05-03 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Genetic Services Laboratory, University of Chicago RCV000049153 SCV002072425 likely benign not specified 2021-12-22 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000162818 SCV002537914 likely benign Hereditary cancer-predisposing syndrome 2022-01-06 criteria provided, single submitter curation
University of Washington Department of Laboratory Medicine, University of Washington RCV000162818 SCV003847921 likely benign Hereditary cancer-predisposing syndrome 2023-03-23 criteria provided, single submitter curation Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673).
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000049153 SCV004026804 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112794 SCV000145691 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Fulgent Genetics, Fulgent Genetics RCV000112794 SCV000575700 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2015-08-07 flagged submission clinical testing
3DMed Clinical Laboratory Inc RCV000677812 SCV000803971 likely benign Cancer of the pancreas 2018-05-21 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001357698 SCV001553244 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA1 p.Val271Met variant has been observed in the literature in 4/1586 proband chromosomes of individuals with sporadic breast cancer. It was also found in 6/334 control chromosomes evaluated (Abkevich 2004, Judkins 2005, Han 2006). In one of these studies that sequenced BRCA1 in a large data set of 55,630 patients, the variant was observed to co-occur with another known deleterious BRCA1 mutation (p.L63X) in trans, increasing the likelihood that the p.Val271Met variant does not have any clinical significance. It is listed in the dbSNP (ID: rs80357244) as coming from a clinical source with a MAF score of 0.001, though it was only observed in one chromosome in the 1000 Genomes study. The p.Val271 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Val271Met variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. The variant was also reported in the BIC database (x4) as a variant with unknown clinical significance and in the LOVD database in 2 studies that predict the variant to be neutral or of little clinical significance. In summary, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more benign role for this variant. This variant is classified as Predicted Benign.
Center for Precision Medicine, Meizhou People's Hospital RCV002250548 SCV002520906 likely benign Familial cancer of breast no assertion criteria provided literature only
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University RCV003153340 SCV003843757 likely pathogenic Ovarian cancer 2022-01-01 flagged submission clinical testing

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