Submissions for variant NM_007294.4(BRCA1):c.5285G>T (p.Arg1762Met)

dbSNP: rs398122694

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130276	SCV000185121	likely benign	Hereditary cancer-predisposing syndrome	2021-03-11	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	RCV000077163	SCV000489352	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2016-09-27	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130276	SCV000683282	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with methionine at codon 1762 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study has reported that this variant does not impact BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in 1 individual age 70 years or older without cancer in the FLOSSIES database. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001843474	SCV002102640	uncertain significance	not provided	2022-02-25	criteria provided, single submitter	clinical testing	Published functional studies demonstrate no damaging effect: variant classified as functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 5404G>T; This variant is associated with the following publications: (PMID: 30209399)
Invitae	RCV001854358	SCV002169079	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 1762 of the BRCA1 protein (p.Arg1762Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 91646). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is not expected to disrupt BRCA1 function with a negative predictive value of 95%. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP)	RCV000077163	SCV000108960	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2013-02-06	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000077163	SCV001242573	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro