ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.811G>A (p.Val271Met) (rs80357244)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195348 SCV000077166 benign Hereditary breast and ovarian cancer syndrome 2020-12-04 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 and 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 Co-occurence with mutation in same gene (phase unknown);No disease association in small case-control study
Fulgent Genetics,Fulgent Genetics RCV000112794 SCV000575700 uncertain significance Breast-ovarian cancer, familial 1 2015-08-07 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000049153 SCV000600438 likely benign not specified 2017-02-04 criteria provided, single submitter clinical testing
Counsyl RCV000112794 SCV000785269 likely benign Breast-ovarian cancer, familial 1 2017-06-23 criteria provided, single submitter clinical testing
Mendelics RCV000195348 SCV000839293 benign Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000758849 SCV000887736 likely benign not provided 2017-02-04 criteria provided, single submitter clinical testing
Color Health, Inc 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 likely benign not specified 2018-02-02 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 observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer 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 predominantly in East Asian individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for causality. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.188T>A, p.Leu63Ter; BRCA1, L63X), providing supporting evidence for a benign role. A massively parallel assay reports the variant to have similar to wild-type E3 ubiquitin ligase activity, however homology-directed DNA repair predictions for this variant were not provided (Starita_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 which range in classification from VUS to benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics RCV000112794 SCV001140620 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000112794 SCV001280987 likely benign Breast-ovarian cancer, familial 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112794 SCV000145691 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided 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.

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