Submissions for variant NM_000059.4(BRCA2):c.7939C>G (p.Leu2647Val)

dbSNP: rs778391123

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165643	SCV000216379	uncertain significance	Hereditary cancer-predisposing syndrome	2024-05-08	criteria provided, single submitter	clinical testing	The p.L2647V variant (also known as c.7939C>G), located in coding exon 16 of the BRCA2 gene, results from a C to G substitution at nucleotide position 7939. The leucine at codon 2647 is replaced by valine, an amino acid with highly similar properties. This alteration was detected in a woman with a personal history of early onset breast cancer (Byers H et al. Eur. J. Hum. Genet., 2016 11;24:1591-1597). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	RCV000466343	SCV000549753	likely benign	Hereditary breast ovarian cancer syndrome	2024-06-14	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000731869	SCV000859731	uncertain significance	not provided	2018-03-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165643	SCV000906564	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-02	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 2647 in the DNA binding domain of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant has been reported to be functional in a haploidized cell proliferation assay (PMID: 35190686). This variant has been reported in an individual affected with breast cancer and in an unaffected individual (PMID: 27273131, 33471991; Leiden Open Variation Database DB-ID BRCA2_003789). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different missense variant at the same amino acid position, p.Leu2647Pro, is considered to be disease-causing (ClinVar variation ID: 52443), suggesting that leucine at this position is important for BRCA2 function. 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	RCV000731869	SCV004039716	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Identified in a high-risk breast cancer family (Byers et al., 2016); Published functional studies demonstrate no impact on splicing (Byers et al., 2016); 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 8167C>G; This variant is associated with the following publications: (PMID: 12228710, 27273131)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003387782	SCV004100041	uncertain significance	not specified	2024-04-11	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7939C>G (p.Leu2647Val) results in a conservative amino acid change located in the Breast cancer type 2 susceptibility protein, helical domain (IPR015252) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 1461876 control chromosomes (gnomAD database v4.0.0). This frequency is not significantly higher than estimated for a pathogenic variant in BRCA2 causing Hereditary Breast And Ovarian Cancer Syndrome (1.6e-05 vs 0.00075), allowing no conclusion about variant significance. c.7939C>G has been reported in the literature in at-least one individual affected with female breast cancer and authors classified the variant as VUS (example: Byers_2016). These report(s) 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. The following publication have been ascertained in the context of this evaluation (PMID: 27273131). ClinVar contains an entry for this variant (Variation ID: 186112). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000731869	SCV005625299	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	The BRCA2 c.7939C>G (p.Leu2647Val) variant has been reported in the published literature in an individual with early-onset breast cancer (PMID: 27273131 (2016)) and a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/BRCA2)). 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant.