Submissions for variant NM_000059.4(BRCA2):c.6475C>G (p.Gln2159Glu)

gnomAD frequency: 0.00009  dbSNP: rs398122558

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588031	SCV000210390	uncertain significance	not provided	2023-02-28	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history including breast cancer (Diaz-Zabala et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); Also known as 6703C>G; This variant is associated with the following publications: (PMID: 24793135, 30400234)
Ambry Genetics	RCV000166819	SCV000217633	likely benign	Hereditary cancer-predisposing syndrome	2023-04-25	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	RCV001083727	SCV000254200	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000076967	SCV000488282	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-02-12	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160111	SCV000694977	likely benign	not specified	2023-09-18	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6475C>G (p.Gln2159Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant is not located to any known functional domain, and the Gln2159 amino acid residue occurs in an evolutionarily not constrained region (PMID: 29358731). The variant allele was found at a frequency of 7.9e-05 in 150946 control chromosomes, predominantly at a frequency of 0.00072 within the Latino subpopulation in the gnomAD database (v3.1 genomes dataset). This frequency is comparable to the estimated maximum expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer Syndrome (0.00075), suggesting that the variant might be benign. The variant, c.6475C>G, has been reported in the literature in two Puerto Rican breast cancer patients (Diaz-Zabala_2018). However, 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. The following publication have been ascertained in the context of this evaluation (PMID: 30400234). Seven other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely benign (n=4) or VUS (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588031	SCV000887883	uncertain significance	not provided	2023-03-24	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMID: 30400234 (2018)) and rhabdomyosarcoma (PMID: 24793135 (2014)). The frequency of this variant in the general population, 0.000067 (2/261556 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000166819	SCV000903842	likely benign	Hereditary cancer-predisposing syndrome	2017-05-11	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000166819	SCV003852565	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).
Sharing Clinical Reports Project (SCRP)	RCV000076967	SCV000108764	benign	Breast-ovarian cancer, familial, susceptibility to, 2	2013-09-24	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004732649	SCV005362841	uncertain significance	BRCA2-related disorder	2024-08-04	no assertion criteria provided	clinical testing	The BRCA2 c.6475C>G variant is predicted to result in the amino acid substitution p.Gln2159Glu. This variant has been reported in two Puerto Rican individuals with breast cancer, although no further evidence was provided to determine its pathogenicity (Table 2, Diaz-Zabala et al. 2018. PubMed ID: 30400234). It has also been reported in a rhabdomyosarcoma specimen (Table S3, Kohsaka et al. 2014. PubMed ID: 24793135). This variant is reported in 2 of ~262,000 alleles in gnomAD v2 and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/91450/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.