Submissions for variant NM_000059.4(BRCA2):c.5900A>G (p.Lys1967Arg)

dbSNP: rs959089047

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000487031	SCV000564788	uncertain significance	not provided	2018-08-24	criteria provided, single submitter	clinical testing	This variant is denoted BRCA2 c.5900A>G at the cDNA level, p.Lys1967Arg (K1967R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). Using alternate nomenclature, this variant would be defined as BRCA2 6128A>G. This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. BRCA2 Lys1967Arg was not observed in large population cohorts (Lek 2016). This variant is located in the RAD51 Binding Domain (Roy 2012). While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a new splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether BRCA2 Lys1967Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000553708	SCV000635479	uncertain significance	Hereditary breast ovarian cancer syndrome	2024-11-17	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 1967 of the BRCA2 protein (p.Lys1967Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with ovarian cancer (PMID: 33273034). ClinVar contains an entry for this variant (Variation ID: 418085). 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	RCV000563594	SCV000668673	likely benign	Hereditary cancer-predisposing syndrome	2024-12-05	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.
Color Diagnostics, LLC DBA Color Health	RCV000563594	SCV000683740	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1967 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 an individual affected with ovarian cancer and in one unaffected individual (PMID: 33273034, 33471991; Leiden Open Variation Database DB-ID BRCA2_002903). 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.
Sema4, Sema4	RCV000563594	SCV002536186	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	curation
University of Washington Department of Laboratory Medicine, University of Washington	RCV000563594	SCV003850764	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	RCV003493591	SCV004846664	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with arginine at codon 1967 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 an individual affected with ovarian cancer and in one unaffected individual (PMID: 33273034, 33471991; Leiden Open Variation Database DB-ID BRCA2_002903). 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.
BRCAlab, Lund University	RCV003493591	SCV004243695	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2020-03-02	no assertion criteria provided	clinical testing