Submissions for variant NM_000059.4(BRCA2):c.8633-4T>A

dbSNP: rs397507407

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122935	SCV000166193	likely benign	Hereditary breast ovarian cancer syndrome	2025-01-07	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000132191	SCV000187271	likely benign	Hereditary cancer-predisposing syndrome	2021-11-05	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.
GeneDx	RCV000442944	SCV000520390	likely benign	not specified	2015-10-27	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.
Color Diagnostics, LLC DBA Color Health	RCV000132191	SCV000689142	likely benign	Hereditary cancer-predisposing syndrome	2023-12-28	criteria provided, single submitter	clinical testing
Counsyl	RCV000031756	SCV000785839	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2017-12-18	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237417	SCV002010304	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442944	SCV004037937	uncertain significance	not specified	2023-08-17	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8633-4T>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251110 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8633-4T>A has been reported in the literature in individuals taking BRCA1/BRCA2 or multiple cancer gene screenings without strong evidence for causality (examples, Lincoln_2015, Caux-Moncoutier_2011). 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 publications have been ascertained in the context of this evaluation (PMID: 21120943, 26207792). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=3; Likely benign, n=3). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003237417	SCV005625329	uncertain significance	not provided	2024-06-27	criteria provided, single submitter	clinical testing	The BRCA2 c.8633-4T>A variant has been reported in the published literature in individuals with a personal and/or family history of breast and/or ovarian cancer who underwent multi-gene panel testing (PMID: 21120943 (2011), and 26207792 (2015)). The frequency of this variant in the general population, 0.000004 (1/251110 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.
Sharing Clinical Reports Project (SCRP)	RCV000031756	SCV000054364	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2011-03-21	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353567	SCV000592218	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.8633-4T>A variant was identified in the literature in at least one proband with hereditary breast or ovarian cancer (Caux-Moncoutier 2011), and was listed once in UMD as an unclassified variant. The variant is located in the 3' splice region of BRCA2 intron 20 but does not affect the highly conserved -1 and -2 positions.  Positions -3 and -5 to -12 are also part of the splicing consensus sequence and variants involving these positions sometimes affect splicing; however, this variant is located at position -4 which is outside of the splicing consensus sequence and where the nucleotide present may vary. In addition, three in silico or computational prediction software programs (MaxEntScan, NNSPLICE, HumanSpliceFinder) do not predict a difference in splicing; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of unknown significance.