ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7618-16T>G (rs397507924)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045264 SCV000073277 likely benign Hereditary breast and ovarian cancer syndrome 2016-12-30 criteria provided, single submitter clinical testing
GeneDx RCV000235946 SCV000293935 uncertain significance not provided 2016-02-09 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7618-16T>G or IVS15-16T>G and consists of a T>G nucleotide substitution at the -16 position of intron 15 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7846-16T>G. Multiple in silico models predict this variant to weaken the nearby natural acceptor site, and to possibly cause abnormal gene splicing; however, in the absence of RNA or functional studies, the actual effect of this variant is unknown. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 c.7618-16T>G was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. The thymine (T) nucleotide that is altered is not conserved across species. Based on currently available information, it is unclear whether BRCA2 c.7618-16T>G is pathogenic or benign.
Color RCV000771917 SCV000904697 likely benign Hereditary cancer-predisposing syndrome 2015-04-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781058 SCV000918849 uncertain significance not specified 2018-06-01 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.7618-16T>G 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. Several computational tools predict a significant impact on normal splicing: one predicts that the variant abolishes a 3 prime acceptor site, and two predict the weakening of the 3 prime acceptor site. An in silico study also predicted that the variant of interest weakens a natural splicing site (Mucaki 2011). However, these predictions have yet to be confirmed by functional studies. The variant was absent in 243754 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.7618-16T>G in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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