Submissions for variant NM_000059.4(BRCA2):c.413G>T (p.Cys138Phe)

gnomAD frequency: 0.00001  dbSNP: rs397507324

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129991	SCV000184815	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-09	criteria provided, single submitter	clinical testing	The p.C138F variant (also known as c.413G>T), located in coding exon 3 of the BRCA2 gene, results from a G to T substitution at nucleotide position 413. The cysteine at codon 138 is replaced by phenylalanine, 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.
GeneDx	RCV000160017	SCV000210236	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; Also known as 641G>T; This variant is associated with the following publications: (PMID: 32377563, 29884841)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637505	SCV000758966	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-09-23	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 138 of the BRCA2 protein (p.Cys138Phe). This variant is not present in population databases (gnomAD no frequency). 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: 37882). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000779935	SCV000916876	uncertain significance	not specified	2024-11-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.413G>T (p.Cys138Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250262 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.413G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 37882). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003473170	SCV004211817	uncertain significance	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000031463	SCV004846770	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-23	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with phenylalanine at codon 138 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: 33471991; Leiden Open Variation Database DB-ID BRCA2_007708). This variant has been identified in 1/250262 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160017	SCV005624419	uncertain significance	not provided	2024-05-01	criteria provided, single submitter	clinical testing	The BRCA2 c.413G>T (p.Cys138Phe) variant has been reported in the published literature in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)), as well as in individuals undergoing multigene panel testing (PMID: 31853058 (2020)). The frequency of this variant in the general population, 0.000004 (1/250262 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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.
Sharing Clinical Reports Project (SCRP)	RCV000031463	SCV000054068	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2010-01-26	no assertion criteria provided	clinical testing