Submissions for variant NM_000059.4(BRCA2):c.8386C>T (p.Pro2796Ser)

gnomAD frequency: 0.00002  dbSNP: rs146120136

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130261	SCV000185105	likely benign	Hereditary cancer-predisposing syndrome	2019-03-26	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000226735	SCV000283341	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-27	criteria provided, single submitter	clinical testing
GeneDx	RCV000586491	SCV000516170	likely benign	not provided	2018-12-26	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 25428789, 24094589, 22505045, 30254663, 30263092)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586491	SCV000600801	uncertain significance	not provided	2023-07-06	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in individuals with breast cancer (PMID: 30254663 (2018), 34011307 (2021)) and reported to have no deleterious effect on BRCA2 mRNA splicing (PMID: 22505045 (2012)). In a large-scale breast cancer association study, the variant was observed in an individual with breast cancer as well as in unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/BRCA2)). The frequency of this variant in the general population, 0.000035 (4/113728 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586491	SCV000695148	uncertain significance	not provided	2017-07-06	criteria provided, single submitter	clinical testing	Variant summary: The c.8386C>T (p.Pro2796Ser) in BRCA2 gene is a missense variant involves a non-conserved nucleotide and 3/5 in silico tools predict benign outcome. The variant is located within the close proximity to the second OB fold (OB2) of the 800-amino acid C-terminal ssDNA binding domain (DBD) of BRCA2, however no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. The variant was proven to not affect splicing. The variant is present at a low frequencies in the control population datasets of ExAC and gnomAD (1.647e-05; 2/121408 and 4/246222 chrs tested, respectively). These frequencies do not exceed the maximal expected allele frequency for a disease causing allele in BRCA2 gene (0.000175). The variant has been reported in several affected individuals via published reports without strong evidence for causality. Lastly, several reputable databases/clinical laboratories have classified the variant as VUS/Likely Benign. Taken together, the variant was classified as VUS, until new information becomes available.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000735611	SCV000901123	uncertain significance	Breast and/or ovarian cancer	2017-06-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130261	SCV000903472	benign	Hereditary cancer-predisposing syndrome	2016-04-26	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000226735	SCV004228035	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-11-21	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000077028	SCV000108825	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2011-04-19	no assertion criteria provided	clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research	RCV000735611	SCV000863749	uncertain significance	Breast and/or ovarian cancer		no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000077028	SCV004228450	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	BP5(Moderate) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)