Submissions for variant NM_007294.4(BRCA1):c.2638G>C (p.Glu880Gln)

dbSNP: rs587782370

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131341	SCV000186316	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-10	criteria provided, single submitter	clinical testing	The p.E880Q variant (also known as c.2638G>C), located in coding exon 9 of the BRCA1 gene, results from a G to C substitution at nucleotide position 2638. The glutamic acid at codon 880 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001222005	SCV001394084	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-19	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 142303). 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. 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. This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 880 of the BRCA1 protein (p.Glu880Gln).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284391	SCV001470164	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in an individual with breast cancer (PMID: 34196900 (2021)) and an unspecified phenotype (PMID: 34413315 (2021)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001328387	SCV001519510	uncertain significance	not specified	2023-03-13	criteria provided, single submitter	clinical testing	Variant summary: BRCA1 c.2638G>C (p.Glu880Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251128 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2638G>C has been reported in the literature in the settings of multigene panel testing for cancer, without strong evidence for causality (Ren_2021, Herzog_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001284391	SCV001821108	uncertain significance	not provided	2020-02-14	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as c.2757G>C
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131341	SCV003851018	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).