Submissions for variant NM_000059.4(BRCA2):c.1706A>G (p.Gln569Arg)

dbSNP: rs1566224153

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000704219	SCV000833158	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 569 of the BRCA2 protein (p.Gln569Arg). 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. 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. ClinVar contains an entry for this variant (Variation ID: 580625). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency).
Color Diagnostics, LLC DBA Color Health	RCV001184333	SCV001350293	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 569 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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	RCV001184333	SCV003851583	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).
Ambry Genetics	RCV001184333	SCV005025146	likely benign	Hereditary cancer-predisposing syndrome	2024-02-02	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.
All of Us Research Program, National Institutes of Health	RCV004802394	SCV005424295	uncertain significance	BRCA2-related cancer predisposition	2024-03-24	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 569 of the BRCA2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.