ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7618-6G>T (rs1057520251)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000425986 SCV000512388 likely benign not specified 2016-08-01 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.
Invitae RCV000943678 SCV001089631 likely benign not provided 2018-09-26 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000425986 SCV001339007 uncertain significance not specified 2020-03-23 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7618-6G>T 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. Experimental evidence supports these predictions indicating no effect on splicing following cDNA analysis in patient samples (Baert_2018). The variant was absent in 249062 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.7618-6G>T has been reported in the literature in at least one individual affected with Hereditary Breast and Ovarian Cancer (e.g. Bosdet_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Two ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000943678 SCV000592131 uncertain significance not provided no assertion criteria provided clinical testing The c.7618-6G>T variant has not been previously observed in the literature, nor has it been or been reported in the LOVD, Exome Variant Server or UMD databases. The variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. Computational or in-silico analyses do not demonstrate altered splicing in any of the splice prediction programs (SpliceSiteFinder-like, MaxEntScan, NNSPLICE, HumanSpliceFinder, GeneSplicer), increasing the possibility that this may be a benign variant. 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 at this time. Therefore this variant is a variant of unknown significance.

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