Submissions for variant NM_000059.4(BRCA2):c.9409A>T (p.Thr3137Ser)

dbSNP: rs746036918

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781069	SCV000918873	uncertain significance	not specified	2023-11-08	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.9409A>T (p.Thr3137Ser) results in a conservative amino acid change located in the BRCA2, OB3 domain of 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 251354 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9409A>T has been reported in the literature as a VUS in settings of multigene panel testing in individuals undergoing testing for breast/ovarian cancer (e.g. Tung_2014, Zuntini_2018, Singh_2018, Fanale_2022) and in an individual affected with Li Fraumeni syndrome carrying pathogenic variants in other genes (e.g. Caliskan_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (ATM c.5979_5983delTAAAG, p.Ser1993ArgfsX23; TP53 c.700T>C, p.Tyr234His), providing supporting evidence for a potential benign role (e.g. Caliskan_2023). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36367123, 35150867, 29470806, 25186627, 30254663). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV001189739	SCV001357094	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-03	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 3137 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with breast cancer and another individual at familial risk of breast and ovarian cancer (PMID: 25186627, 30254663). This variant has been identified in 1/251354 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001350894	SCV001545322	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-02	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 3137 of the BRCA2 protein (p.Thr3137Ser). This variant is present in population databases (rs746036918, gnomAD 0.003%). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 25186627, 29470806, 30254663, 35150867). ClinVar contains an entry for this variant (Variation ID: 633109). 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.
GeneDx	RCV001563090	SCV001785970	uncertain significance	not provided	2021-12-03	criteria provided, single submitter	clinical testing	Observed in individuals with a personal and/or family history of breast and/or ovarian cancer (Tung 2015, Singh 2018, Zuntini 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9637A>T; This variant is associated with the following publications: (PMID: 29470806, 30254663, 25186627, 12228710)
Ambry Genetics	RCV001189739	SCV002686448	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-17	criteria provided, single submitter	clinical testing	The p.T3137S variant (also known as c.9409A>T), located in coding exon 24 of the BRCA2 gene, results from an A to T substitution at nucleotide position 9409. The threonine at codon 3137 is replaced by serine, an amino acid with similar properties. This alteration has been identified in multiple individuals diagnosed with breast and/or ovarian cancer (Tung N et al. Cancer, 2015 Jan;121:25-33; Singh J et al. Breast Cancer Res. Treat., 2018 Jul;170:189-196; Zuntini R et al. Front Genet, 2018 Sep;9:378). This amino acid position is 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001563090	SCV002774488	uncertain significance	not provided	2021-06-21	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV001563090	SCV003830151	uncertain significance	not provided	2021-09-22	criteria provided, single submitter	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV003483720	SCV004228300	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+BP4(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)