Submissions for variant NM_000059.4(BRCA2):c.7095T>A (p.His2365Gln)

dbSNP: rs370708814

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000200353	SCV000254205	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 2365 of the BRCA2 protein (p.His2365Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with lung adenocarcinoma (PMID: 26689913, 28843361). ClinVar contains an entry for this variant (Variation ID: 216255). 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.
Ambry Genetics	RCV000222104	SCV000277367	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-15	criteria provided, single submitter	clinical testing	The p.H2365Q variant (also known as c.7095T>A), located in coding exon 13 of the BRCA2 gene, results from a T to A substitution at nucleotide position 7095. The histidine at codon 2365 is replaced by glutamine, an amino acid with highly similar 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000768606	SCV000324873	uncertain significance	Breast and/or ovarian cancer	2019-04-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222104	SCV000906544	uncertain significance	Hereditary cancer-predisposing syndrome	2019-05-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193840	SCV001362986	uncertain significance	not specified	2019-04-15	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7095T>A (p.His2365Gln) 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 allele was found at a frequency of 4e-06 in 251012 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7095T>A has been reported in the literature in individuals affected with lung adenocarcinoma (Parry_2017, Lu_NatCommun_2015). However, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant have been reported (BRCA1 c.5080G>T, p.Glu1694X), providing supporting evidence for a benign role (UMD database). 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.
GeneDx	RCV001565170	SCV001788464	uncertain significance	not provided	2022-01-28	criteria provided, single submitter	clinical testing	Observed in individuals with lung cancer (Lu 2015, Parry 2017); 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 7323T>A; This variant is associated with the following publications: (PMID: 26689913, 28843361)
Baylor Genetics	RCV003462319	SCV004213664	uncertain significance	Familial cancer of breast	2023-08-17	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001565170	SCV004220543	uncertain significance	not provided	2023-06-09	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with lung cancer (PMID: 28843361 (2017), 26689913 (2015)). The variant has also been reported in an elderly cancer free female (PMID: 32658311 (2021)). The frequency of this variant in the general population, 0.000004 (1/251012 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.
MGZ Medical Genetics Center	RCV003462319	SCV004543915	likely benign	Familial cancer of breast	2024-02-09	criteria provided, single submitter	clinical testing	ACMG codes applied following ENIGMA VCEP rules: BP1_STR, PM2_SUP
PreventionGenetics, part of Exact Sciences	RCV003895269	SCV004708498	uncertain significance	BRCA2-related condition	2024-01-18	criteria provided, single submitter	clinical testing	The BRCA2 c.7095T>A variant is predicted to result in the amino acid substitution p.His2365Gln. This variant has been observed in individuals with lung adenocarcinoma (Supp. Data 12, Lu et al. 2015. PubMed ID: 26689913; Table S1, Parry et al. 2017. PubMed ID: 28843361). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/216255/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.