Submissions for variant NM_000059.4(BRCA2):c.6121T>A (p.Ser2041Thr)

dbSNP: rs1160083526

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000575027	SCV000661394	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-18	criteria provided, single submitter	clinical testing	The p.S2041T variant (also known as c.6121T>A), located in coding exon 10 of the BRCA2 gene, results from a T to A substitution at nucleotide position 6121. The serine at codon 2041 is replaced by threonine, 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	RCV000808364	SCV000948471	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-12-02	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 2041 of the BRCA2 protein (p.Ser2041Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast and ovarian cancer (PMID: 35918668). ClinVar contains an entry for this variant (Variation ID: 479374). 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	RCV000575027	SCV001353126	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 2041 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 not been reported in individuals affected with BRCA2-related disorders in the literature. 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	RCV002509439	SCV002819450	uncertain significance	not specified	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6121T>A (p.Ser2041Thr) results in a conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250808 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6121T>A has been reported in the literature in individuals affected with Benign Breast Disease (Suter_2004). This report does 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. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000575027	SCV003850953	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).
All of Us Research Program, National Institutes of Health	RCV004000831	SCV004846704	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with threonine at codon 2041 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 not been reported in individuals affected with BRCA2-related disorders in the literature. 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.
Center for Precision Medicine, Meizhou People's Hospital	RCV002250658	SCV002520816	uncertain significance	Familial cancer of breast		no assertion criteria provided	curation