Submissions for variant NM_000059.4(BRCA2):c.8332-6G>T

gnomAD frequency: 0.00001  dbSNP: rs587780872

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000124008	SCV000167410	benign	not specified	2014-02-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000456541	SCV000560395	likely benign	Hereditary breast ovarian cancer syndrome	2024-01-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477532	SCV000600794	uncertain significance	not provided	2023-01-17	criteria provided, single submitter	clinical testing	To the best of our knowledge, this variant has not been reported in individuals with BRCA2-related conditions in the published literature. The frequency of this variant in the general population, 0.000012 (3/251374 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant does not affect BRCA2 mRNA splicing . Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000580592	SCV000683958	likely benign	Hereditary cancer-predisposing syndrome	2016-09-12	criteria provided, single submitter	clinical testing
Counsyl	RCV000663037	SCV000786076	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-02-20	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000124008	SCV000919022	uncertain significance	not specified	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8332-6G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/4 computational tools predict no significant impact on normal splicing, while 1 predicts a strengthening of the 3' splice acceptor site and 1 predicts a weakening or loss of this site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251374 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8332-6G>T in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, classifying it as likely benign (n=3) and VUS (n=1). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Ambry Genetics	RCV000580592	SCV002677158	likely benign	Hereditary cancer-predisposing syndrome	2014-07-23	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.
PreventionGenetics, part of Exact Sciences	RCV004530070	SCV004709392	likely benign	BRCA2-related disorder	2020-10-09	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).