Submissions for variant NM_000059.4(BRCA2):c.6614T>G (p.Val2205Gly)

dbSNP: rs730881546

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160116	SCV000210397	uncertain significance	not provided	2024-11-03	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6842T>G; This variant is associated with the following publications: (PMID: 25186627, 30287823, 31228304, 37415649, 36243179, 35753294)
Ambry Genetics	RCV000509910	SCV000607824	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing	The p.V2205G variant (also known as c.6614T>G), located in coding exon 10 of the BRCA2 gene, results from a T to G substitution at nucleotide position 6614. The valine at codon 2205 is replaced by glycine, an amino acid with dissimilar properties. This alteration was identified in multiple individuals diagnosed with breast cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Bisgin A et al. Breast J, 2019 Sep;25:1029-1033; Boga I et al. Eur J Breast Health, 2023 Jul;19:235-252). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637443	SCV000758902	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2205 of the BRCA2 protein (p.Val2205Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627, 31228304). ClinVar contains an entry for this variant (Variation ID: 182229). 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.
Color Diagnostics, LLC DBA Color Health	RCV000509910	SCV001355519	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553668	SCV001774608	uncertain significance	not specified	2021-08-01	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6614T>G (p.Val2205Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 245262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6614T>G has been reported in the literature in individuals affected with breast cancer undergoing multigene panel testing as well as in unaffected controls (example, Tung_2015, Momozawa_2018, Bisgin_2019). 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. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160116	SCV002046982	uncertain significance	not provided	2024-02-07	criteria provided, single submitter	clinical testing	The BRCA2 c.6614T>G (p.Val2205Gly) variant has been reported in the published literature in individuals with a personal or family history of breast cancer (PMIDs: 37415649 (2023), 31228304 (2019), 25186627 (2015)), as well as in reportedly healthy individuals (PMIDs: 31214711 (2020), 30287823 (2018)). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509910	SCV003847314	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).