Submissions for variant NM_000059.4(BRCA2):c.3644G>A (p.Gly1215Glu)

gnomAD frequency: 0.00001  dbSNP: rs773442698

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000556462	SCV000635297	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-03-16	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 1215 of the BRCA2 protein (p.Gly1215Glu). This variant is present in population databases (rs773442698, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462303). 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 BRCA2 protein function with a negative predictive value of 95%. 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.
Ambry Genetics	RCV000571908	SCV000664810	likely benign	Hereditary cancer-predisposing syndrome	2018-05-29	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.
Color Diagnostics, LLC DBA Color Health	RCV000571908	SCV001346144	uncertain significance	Hereditary cancer-predisposing syndrome	2020-02-03	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 1215 of the BRCA2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250596 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.
Genetics and Molecular Pathology, SA Pathology	RCV002272282	SCV002556521	uncertain significance	Ovarian neoplasm	2020-08-10	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000571908	SCV003846759	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).
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003478145	SCV004219598	uncertain significance	not provided	2023-03-03	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000008 (2/250596 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In a breast cancer association study, the variant was observed in a breast cancer case and in a control individual (PMID: 33471991 (2021)). 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.