Submissions for variant NM_007294.4(BRCA1):c.5343A>C (p.Glu1781Asp)

dbSNP: rs1555575182

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000581039	SCV000683300	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 1781 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781018	SCV000918772	uncertain significance	not specified	2018-08-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.5343A>C (p.Glu1781Asp) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 246218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.5343A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission from another clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertain significance." Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV000804010	SCV000943900	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-02-09	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 1781 of the BRCA1 protein (p.Glu1781Asp). This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change does not substantially affect BRCA1 function (PMID: 30209399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt BRCA1 protein function. ClinVar contains an entry for this variant (Variation ID: 489730). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions.
Ambry Genetics	RCV000581039	SCV002645042	likely benign	Hereditary cancer-predisposing syndrome	2022-10-27	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.
Brotman Baty Institute, University of Washington	RCV001077241	SCV001243140	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro