ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6938-2A>G (rs81002863)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000083132 SCV001161656 pathogenic Breast-ovarian cancer, familial 2 2019-06-18 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.994607
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000083132 SCV000327543 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000479362 SCV000567943 pathogenic not provided 2017-05-24 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6938-2A>G or IVS12-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 12 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 7166-2A>G. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. Based on the currently available information, we consider BRCA2 c.6938-2A>G to be a pathogenic variant.
Ambry Genetics RCV000509741 SCV000608224 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-19 criteria provided, single submitter clinical testing The c.6938-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 12 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779943 SCV000916886 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-20 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6938-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing, resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 244092 control chromosomes. The c.6938-2A>G variant has been reported in the literature in one individual affected with Hereditary Breast and Ovarian Cancer. This report does not provide unequivocal conclusions about an association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and all laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae RCV000779943 SCV001577441 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-06 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 12 of the BRCA2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals in the Leiden Open-source Variation Database (PMID: 21520333) and Breast Cancer Information Core database (PMID: 10923033). ClinVar contains an entry for this variant (Variation ID: 52222). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA2 are known to be pathogenic (PMID: 20104584). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000083132 SCV000115206 likely pathogenic Breast-ovarian cancer, familial 2 2011-01-14 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000083132 SCV000146973 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735592 SCV000863730 likely pathogenic Breast and/or ovarian cancer no assertion criteria provided clinical testing

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