Submissions for variant NM_007294.4(BRCA1):c.5198A>G (p.Asp1733Gly)

dbSNP: rs80357270

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000112560	SCV001161598	benign	Breast-ovarian cancer, familial, susceptibility to, 1	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.000577
Labcorp Genetics (formerly Invitae), Labcorp	RCV001088030	SCV000076867	likely benign	Hereditary breast ovarian cancer syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129798	SCV000184607	likely benign	Hereditary cancer-predisposing syndrome	2018-09-11	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.
GeneDx	RCV000417372	SCV000209987	likely benign	not specified	2018-02-14	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000417372	SCV000699212	benign	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5198A>G (p.Asp1733Gly) results in a non-conservative amino acid change located in the BRCT domain (IPR001357) of 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 2e-05 in 251488 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5198A>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (e.g. Judkins_2005, Tavtigian_2006). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with other pathogenic variants (such as BRCA1 c.1059G>A, p.Trp353Ter) have been reported in the BIC database and in publication (Tavtigian_2006), providing supporting evidence for a benign role. In addition, multiple functional studies report comparable transcriptional activity and other properties between the variant and wild-type. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (Benign/likely benign n=7, VUS n=1). Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590656	SCV000888942	likely benign	not provided	2020-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129798	SCV000903063	benign	Hereditary cancer-predisposing syndrome	2015-11-09	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590656	SCV002049434	likely benign	not provided	2021-07-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000417372	SCV002069338	uncertain significance	not specified	2018-07-12	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV001088030	SCV005045385	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-01-23	criteria provided, single submitter	clinical testing
Breast Cancer Information Core (BIC) (BRCA1)	RCV000112560	SCV000145389	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2004-02-20	no assertion criteria provided	clinical testing
Brotman Baty Institute, University of Washington	RCV000112560	SCV001242875	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro
emedgene Technologies	RCV000112560	SCV001774875	benign	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion criteria provided	not provided
PreventionGenetics, part of Exact Sciences	RCV004554688	SCV004773644	benign	BRCA1-related disorder	2022-05-03	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).