Submissions for variant NM_000059.4(BRCA2):c.6125A>C (p.Gln2042Pro)

dbSNP: rs80358852

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203091	SCV000072864	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-20	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000131951	SCV000187008	benign	Hereditary cancer-predisposing syndrome	2016-07-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000203091	SCV000257613	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-06-08	criteria provided, single submitter	clinical testing
Counsyl	RCV000031599	SCV000488344	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2016-03-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265571	SCV000694940	uncertain significance	not specified	2023-08-29	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.6125A>C (p.Gln2042Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250934 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.6125A>C has been reported in the literature as a class 3 (VUS) variant in at-least one individual with breast/ovarian cancer (example, Mehta_2018). These report(s) do 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: 30555256). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (Benign/Likely benign, n=2, VUS, n=5). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000203091	SCV000838833	uncertain significance	Hereditary breast ovarian cancer syndrome	2018-07-02	criteria provided, single submitter	clinical testing
GeneDx	RCV000587844	SCV001823729	uncertain significance	not provided	2024-12-05	criteria provided, single submitter	clinical testing	In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (PMID: 30555256); Also known as 6353A>C; This variant is associated with the following publications: (PMID: Ahamad2020[article], 29884841, 31911673, 32377563, 30555256)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000131951	SCV003850957	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	RCV004803054	SCV004846707	uncertain significance	BRCA2-related cancer predisposition	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with proline at codon 2042 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 breast cancer (PMID: 30555256). This variant has been identified in 2/282338 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587844	SCV005624486	uncertain significance	not provided	2024-11-29	criteria provided, single submitter	clinical testing	The BRCA2 c.6125A>C (p.Gln2042Pro) variant has been reported in the published literature in an individual with breast and/or ovarian cancer (PMID: 30555256 (2018)), and described to be located in a region of the BRCA2 gene that is tolerant to missense sequence changes (PMID: 31911673 (2020)). The frequency of this variant in the general population, 0.0000071 (2/282338 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the 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.
Sharing Clinical Reports Project (SCRP)	RCV000031599	SCV000054206	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2013-07-25	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000031599	SCV000146773	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2000-06-12	no assertion criteria provided	clinical testing