Submissions for variant NM_000059.4(BRCA2):c.9584C>G (p.Thr3195Ser)

dbSNP: rs431825376

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568260	SCV000673119	uncertain significance	Hereditary cancer-predisposing syndrome	2017-02-08	criteria provided, single submitter	clinical testing	The p.T3195S variant (also known as c.9584C>G), located in coding exon 25 of the BRCA2 gene, results from a C to G substitution at nucleotide position 9584. The threonine at codon 3195 is replaced by serine, an amino acid with similar properties. This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003530080	SCV004297198	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-02	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 3195 of the BRCA2 protein (p.Thr3195Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer (PMID: 27616075, 31451522). ClinVar contains an entry for this variant (Variation ID: 485432). 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.
Color Diagnostics, LLC DBA Color Health	RCV000568260	SCV004362827	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-31	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 3195 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 one individual affected with breast cancer (PMID: 31451522). 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	RCV004787950	SCV005401422	uncertain significance	not provided	2024-05-13	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 9812C>G; This variant is associated with the following publications: (PMID: 27616075, 29884841, 31451522, 32377563)
PreventionGenetics, part of Exact Sciences	RCV004722941	SCV005337864	uncertain significance	BRCA2-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The BRCA2 c.9584C>G variant is predicted to result in the amino acid substitution p.Thr3195Ser. This variant has been reported in an individual with breast cancer and was interpreted as uncertain in the study (Supplemental table 4. Kraus et al 2017. PubMed ID: 27616075). This variant has not been reported in a large population database, indicating this variant is rare. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/485432/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.