Submissions for variant NM_000059.4(BRCA2):c.5945G>C (p.Ser1982Thr)

dbSNP: rs28897738

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203657	SCV000072809	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 1982 of the BRCA2 protein (p.Ser1982Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 20127978). ClinVar contains an entry for this variant (Variation ID: 38010). 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	RCV000590082	SCV000210376	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as 6173G>C; Observed several times in cis with a known pathogenic BRCA2 variant (Chenevix-Trench et al., 2006) and observed in individuals with familial breast cancer (Morgan et al., 2010; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 21702907, 18724707, 16489001, 20127978, 27376475, 20167696, 29884841, 33471991, 32377563, 9002670, 22193408)
Ambry Genetics	RCV000510094	SCV000607808	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-08	criteria provided, single submitter	clinical testing	The p.S1982T variant (also known as c.5945G>C), located in coding exon 10 of the BRCA2 gene, results from a G to C substitution at nucleotide position 5945. The serine at codon 1982 is replaced by threonine, an amino acid with similar properties. 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.
Color Diagnostics, LLC DBA Color Health	RCV000510094	SCV000688958	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-23	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 1982 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals and families affected with breast cancer, some of whom also have a pathogenic BRCA2 covariant (PMID: 16489001, 20127978, 33471991; Leiden Open Variation Database DB-ID BRCA2_003716, kConFab database, Color internal data). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000044796	SCV000694918	uncertain significance	not specified	2024-04-09	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.5945G>C (p.Ser1982Thr) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250700 control chromosomes in gnomAD. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5945G>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer, without strong evidence for causality (example: Chenevix-Trench_2006, Morgan_2010, Schenkel_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. The variant has been observed to co-occur with a pathogenic BRCA2 c.4163_4164delCTinsA in at least 10 individuals (3 internal specimens, 7 BIC individuals) providing supporting evidence for a benign role. 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: 16489001, 21702907, 18724707, 20167696, 20127978, 27376475). ClinVar contains an entry for this variant (Variation ID: 38010). Based on the evidence outlined above, the variant was classified as VUS - possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590082	SCV000889084	uncertain significance	not provided	2023-12-14	criteria provided, single submitter	clinical testing	The BRCA2 c.5945G>C (p.Ser1982Thr) variant has been reported in the published literature in individuals with breast cancer (PMIDs: 33471991 (2021), 20127978 (2010), 16489001 (2006), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). Additionally, the variant described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000510094	SCV002536188	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-12	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000510094	SCV003850806	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).
Breast Cancer Information Core (BIC) (BRCA2)	RCV000113507	SCV000146735	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483440	SCV004228965	not provided	BRCA2-related disorder		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-15-2018 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.