Submissions for variant NM_000059.4(BRCA2):c.3949A>T (p.Thr1317Ser)

dbSNP: rs398122773

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000229385	SCV000283221	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-21	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 1317 of the BRCA2 protein (p.Thr1317Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with personal and/or family history of breast cancer (PMID: 21120943). ClinVar contains an entry for this variant (Variation ID: 91810). 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.
Ambry Genetics	RCV000509876	SCV000608239	likely benign	Hereditary cancer-predisposing syndrome	2024-06-03	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804830	SCV002051433	uncertain significance	not specified	2021-12-31	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.3949A>T (p.Thr1317Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 224038 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3949A>T has been reported in the literature as an unknown variant in settings of BRCA1/BRCA2 testing in a cohort of individuals affected with or a family history of breast cancer (example, Caux-Moncoutier_2011). 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. Two 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000509876	SCV003848551	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).
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV003736569	SCV004563703	uncertain significance	not provided	2023-11-29	criteria provided, single submitter	clinical testing	The BRCA2 c.3949A>T; p.Thr1317Ser variant (rs398122773) is reported in the literature in two individuals with a personal or family history of breast and/or ovarian cancer (Caux-Moncoutier 2011). This variant is reported in ClinVar (Variation ID: 91810) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.206). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Caux-Moncoutier V et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1,525 patients. Hum Mutat. 2011 Mar;32(3):325-34. PMID: 21120943.
All of Us Research Program, National Institutes of Health	RCV000077718	SCV004828077	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with serine at codon 1317 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 individuals with a personal or family history of breast and/or ovarian cancer (PMID: 21120943, 33471991; Leiden Open Variation Database DB-ID BRCA2_002873). 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.
Sharing Clinical Reports Project (SCRP)	RCV000077718	SCV000109521	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2008-05-07	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355525	SCV001550437	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The p.Thr1317Ser variant was identified in 2 of 3050 proband chromosomes (frequency: 0.001) from individuals or families with Breast and Ovarian cancers (Caux-Moncoutier, 2011); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in dbSNP (ID: rs62636281) “With untested allele”, IARC, ClinVar database, and UMD (6X as a class 3-UV variant). The variant was classified as an uncertain variant by the Sharing Clinical Reports Project (SCRP) (submitted within the ClinVar database and derived from Myriad reports). In UMD the variant was identified with a co-occurring “pathogenic” BRCA1 variant (c.IVS5-15A>G (c.213-15A>G)), increasing the likelihood that the p.Thr1317Ser variant does not have clinical significance. Computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign.