Submissions for variant NM_000059.4(BRCA2):c.6181G>A (p.Ala2061Thr)

dbSNP: rs1555284585

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529110	SCV000635494	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-06-30	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2061 of the BRCA2 protein (p.Ala2061Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 462399). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780011	SCV000917002	uncertain significance	not specified	2017-12-18	criteria provided, single submitter	clinical testing	Variant summary:The BRCA2 c.6181G>A (p.Ala2061Thr) variant involves the alteration of a conserved nucleotide, is predicted to be damaging by 4/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index) and is located in BRCA2 repeat 8 which is critical for RAD51 binding (InterPro). This variant is absent in 245114 control chromosomes (gnomAD). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor has it been evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Ambry Genetics	RCV001024975	SCV001187078	uncertain significance	Hereditary cancer-predisposing syndrome	2025-01-22	criteria provided, single submitter	clinical testing	The p.A2061T variant (also known as c.6181G>A), located in coding exon 10 of the BRCA2 gene, results from a G to A substitution at nucleotide position 6181. The alanine at codon 2061 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV001024975	SCV001345508	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-15	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 2061 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in a multifactorial analysis with co-occurrence and family history likelihood ratios for pathogenicity of 1.076 and 0.786, respectively (PMID: 31131967). 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV001024975	SCV003852299	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).
GeneDx	RCV004800451	SCV005421365	uncertain significance	not provided	2024-06-05	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; Has not been previously published as pathogenic or benign to our knowledge; Also known as 6409G>A; This variant is associated with the following publications: (PMID: 31131967, 9002670, 22193408)