Submissions for variant NM_007294.4(BRCA1):c.5260G>C (p.Glu1754Gln)

dbSNP: rs80357432

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000552413	SCV000636023	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 1754 of the BRCA1 protein (p.Glu1754Gln). This variant is present in population databases (rs80357432, gnomAD 0.02%). 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: 462666). 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. 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.
Counsyl	RCV000663140	SCV000786287	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1	2018-04-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000776460	SCV000912005	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glutamine at codon 1754 of the BRCA1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study reported that this variant does not impact BRCA1 function in a haploid cell proliferation assay (PMID: 30209399). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 9/251494 chromosomes 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.
Ambry Genetics	RCV000776460	SCV001185743	benign	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV003238765	SCV003936574	uncertain significance	not provided	2022-12-28	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 5379G>C; Published functional studies demonstrate no damaging effect: variant classified as functional based on a saturation genome editing (SGE) assay measuring cell survival (Findlay et al., 2018); This variant is associated with the following publications: (PMID: 30209399, 10220405, 24389207, 9811458, 9738006, 10196224, 9974970, 11301010, 32377563, 29884841)
Brotman Baty Institute, University of Washington	RCV000663140	SCV001241602	not provided	Breast-ovarian cancer, familial, susceptibility to, 1		no assertion provided	in vitro