Submissions for variant NM_000059.4(BRCA2):c.4960T>G (p.Cys1654Gly)

dbSNP: rs876659012

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218439	SCV000274959	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-17	criteria provided, single submitter	clinical testing	The p.C1654G variant (also known as c.4960T>G and 5188T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 4960. The cysteine at codon 1654 is replaced by glycine, an amino acid with highly dissimilar properties. This amino acid position is not well 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001059418	SCV001224042	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-05-07	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 1654 of the BRCA2 protein (p.Cys1654Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 34178674). ClinVar contains an entry for this variant (Variation ID: 231191). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000218439	SCV003852239	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).
All of Us Research Program, National Institutes of Health	RCV003997886	SCV004829676	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with glycine at codon 1654 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 34178674) and in an unaffected individual (PMID: 33471991). 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.