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

gnomAD frequency: 0.00003  dbSNP: rs80357244

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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: seen in unaffected individuals, 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
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
All of Us Research Program, National Institutes of Health	RCV000112794	SCV004818407	likely benign	Breast-ovarian cancer, familial, susceptibility to, 1	2023-11-30	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	Malignant tumor of 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