Submissions for variant NM_000059.4(BRCA2):c.5808G>A (p.Met1936Ile)

gnomAD frequency: 0.00001  dbSNP: rs759138390

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165123	SCV000215833	likely benign	Hereditary cancer-predisposing syndrome	2019-02-08	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000457784	SCV000549788	uncertain significance	Hereditary breast ovarian cancer syndrome	2025-01-26	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1936 of the BRCA2 protein (p.Met1936Ile). This variant is present in population databases (rs759138390, gnomAD 0.007%). This missense change has been observed in individual(s) with a personal and/or family history of breast/ovarian cancer (PMID: 16683254, 36329109). ClinVar contains an entry for this variant (Variation ID: 185665). 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	RCV000165123	SCV000683736	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-18	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1936 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). 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 reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID: 16683254). This variant has also been identified in 2/250784 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.
Counsyl	RCV000663021	SCV000786042	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001283931	SCV001469441	uncertain significance	not provided	2019-11-29	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818377	SCV002068558	uncertain significance	not specified	2021-02-16	criteria provided, single submitter	clinical testing
Genetics Program, Instituto Nacional de Cancer	RCV000457784	SCV002515127	uncertain significance	Hereditary breast ovarian cancer syndrome	2021-11-01	criteria provided, single submitter	research
GeneDx	RCV001283931	SCV002759218	uncertain significance	not provided	2022-11-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in a family with breast and/or ovarian cancer (van der Hout et al., 2006); Also known as 6036G>A; This variant is associated with the following publications: (PMID: 22622578, 16683254, 32377563, 29884841)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000165123	SCV003850694	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	RCV000663021	SCV004846651	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-28	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with isoleucine at codon 1936 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). 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 reported in an individual with personal and/or family history of breast and/or ovarian cancer (PMID: 16683254). This variant has also been identified in 2/250784 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.
BRCAlab, Lund University	RCV000663021	SCV004243687	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732726	SCV005350475	uncertain significance	BRCA2-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The BRCA2 c.5808G>A variant is predicted to result in the amino acid substitution p.Met1936Ile. This variant has been reported in individuals with a personal and/or family history of breast/ovarian cancer (Table 3. van der Hout et al 2006. PubMed ID: 16683254; Figure 2. Matta et al 2022. PubMed ID: 36329109). However, this variant occurs within a region of the BRCA2 gene that is predicted to be tolerant to missense variation (Table 2, Dines et al. 2020. PubMed ID: 31911673). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD. This variant is interpreted as a variant of uncertain significance or likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/185665/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.