ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.67+1G>T (rs81002796)

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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) RCV000077382 SCV001161560 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 = 0.995729
Invitae RCV000045022 SCV000073035 pathogenic Hereditary breast and ovarian cancer syndrome 2018-04-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 2. It is expected to disrupt mRNA 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 a family affected with breast and/or ovarian cancer (PMID: 12938098). It is also known as IVS2+1G>T in the literature. ClinVar contains an entry for this variant (RCV000077382). 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). Experimental studies have shown that this variant impacts splicing and results in the skipping of exon 2 in the BRCA2 mRNA (PMID: 22505045). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162894 SCV000213381 pathogenic Hereditary cancer-predisposing syndrome 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity,Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000505843 SCV000296749 pathogenic not provided 2015-01-28 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077382 SCV000327502 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045022 SCV000694986 pathogenic Hereditary breast and ovarian cancer syndrome 2019-07-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.67+1G>T 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: Four predict that the variant abolishes a 5 splicing donor site. Experimental evidence demonstrates that this variant affects mRNA splicing by skipping of exon 2 completely (Fraile-Bethencourt_2019, Houdayer_2012). The variant was absent in 250582 control chromosomes (gnomAD). c.67+1G>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Meyer_2003, Rebbeck_2018, Zugazagoitia_2014). These data indicate that the variant is likely to be associated with disease. Five ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Color RCV000162894 SCV000904689 pathogenic Hereditary cancer-predisposing syndrome 2015-03-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077382 SCV000109179 pathogenic Breast-ovarian cancer, familial 2 2011-09-29 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077382 SCV000146094 pathogenic Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing

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