Submissions for variant NM_000059.4(BRCA2):c.6463C>G (p.Leu2155Val)

dbSNP: rs775035051

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000510026	SCV000608071	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-15	criteria provided, single submitter	clinical testing	The p.L2155V variant (also known as c.6463C>G), located in coding exon 10 of the BRCA2 gene, results from a C to G substitution at nucleotide position 6463. The leucine at codon 2155 is replaced by valine, an amino acid with highly similar properties. This alteration was previously reported in 1/278 individuals with early-onset breast cancer (Maxwell KN et al. Genet. Med., 2015 Aug;17:630-8). 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. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000701295	SCV000830088	uncertain significance	Hereditary breast ovarian cancer syndrome	2022-06-25	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 2155 of the BRCA2 protein (p.Leu2155Val). 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 BRCA2 protein function. ClinVar contains an entry for this variant (Variation ID: 441422). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV000510026	SCV002052236	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 2155 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 observed in at least two individuals affected with breast cancer (PMID: 25503501, 33471991; Leiden Open Variation Database DB-ID BRCA2_007420). 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.
GeneDx	RCV002274048	SCV002559349	uncertain significance	not provided	2022-02-04	criteria provided, single submitter	clinical testing	Identified in an individual with early-onset breast cancer (Maxwell et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 6691C>G; This variant is associated with the following publications: (PMID: 25503501)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510026	SCV003852554	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).