ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.426-12_426-8del (rs276174844)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Breast Cancer Information Core (BIC) (BRCA2) RCV000113566 SCV000146817 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000113566 SCV000744382 uncertain significance Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000113566 SCV000733210 uncertain significance Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
GeneDx RCV000044380 SCV000210806 uncertain significance not provided 2019-02-20 criteria provided, single submitter clinical testing Using alternate nomenclature, this variant has previously been published as BRCA2 654-12_654-8delGTTTT and IVS4-12del5. In silico analysis, are inconclusive as to whether the variant alters gene splicing; though, in vitro splicing assays have demonstrated aberrant splicing caused by exon 5 skipping, leading to a truncated BRCA2 protein (Zhang 2009, Sanz 2010, Whiley 2011). However, these studies exhibit the presence of wild type transcript, indicating that the aberrant splicing caused by this variant is incomplete (Zhang 2009, Sanz 2010). This variant was observed in an early onset breast cancer case, in which loss of heterozygosity was observed in the tumor, and in a proband undergoing hereditary cancer testing (Zhang 2009, Farra 2019). This variant was found to co-occur with a pathogenic BRCA2 variant in the Breast Cancer Information Core (BIC) database. The variant was not observed in large population cohorts (Lek 2016).
Integrated Genetics/Laboratory Corporation of America RCV000496561 SCV000919003 uncertain significance not specified 2018-09-25 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.426-12_426-8delGTTTT leads to deletion of five intronic nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing although a recent computational study predicted a high probability of splicing impact (Leman 2018). Several publications reported experimental evidence that this variant affects mRNA splicing, by increasing exon 5 skipping (predicted to result in a frameshift), and consequently decreasing the expression of the full length transcript (Zhang 2009, Sanz 2010, Whiley 2011, Whiley 2014, Lattimore 2018). The variant was absent in 244660 control chromosomes (gnomAD). c.426-12_426-8delGTTTT has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, however without clear co-segregation evidence. Therefore these data do not allow any conclusion about variant significance. Co-occurrences with other potentially pathogenic variants have been reported (BIC database: BRCA2 c.9257-1G>C; Loughrey 2008: BRCA1 c.5152+1G>T), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as a VUS (2x) and Likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.
Invitae RCV000203666 SCV000072393 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-08-07 criteria provided, single submitter clinical testing This sequence change falls in intron 4 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with breast cancer in the Leiden Open-source Variation Database (PMID: 21520333), the Breast Cancer Information Core database (PMID: 10923033) and the literature, as well as in control individuals (PMID: 16162645, 19070627, 26681312). However, in 2 of these individuals pathogenic alleles were also identified in BRCA2, which suggests that this c.426-12_426-8delGTTTT variant was not the primary cause of disease. This variant is also known as c.426-12del5, IVS4-12del5, and 654-12del5 in the literature. ClinVar contains an entry for this variant (Variation ID: 51619). Experimental studies have shown that this deletion results in the skipping of exon 5, producing a truncated BRCA2 protein. However, the partial expression of the wild-type allele suggests that this aberrant splicing mechanism may be inefficient for disease causation (PMID: 19070627, 20215541, 21394826). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496561 SCV000587547 uncertain significance not specified 2014-01-31 no assertion criteria provided research

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