ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7618-1G>A (rs397507389)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131688 SCV000186724 pathogenic Hereditary cancer-predisposing syndrome 2018-03-30 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
Baylor Genetics RCV000474278 SCV000540996 pathogenic Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Color RCV000131688 SCV000683894 pathogenic Hereditary cancer-predisposing syndrome 2017-02-07 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031692 SCV000327695 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031692 SCV000677711 pathogenic Breast-ovarian cancer, familial 2 2015-06-17 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000031692 SCV000244474 pathogenic Breast-ovarian cancer, familial 2 2015-08-10 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 = 1
GeneDx RCV000045265 SCV000210435 pathogenic not provided 2018-10-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.7618-1G>A or IVS15-1G>A and consists of a G>A nucleotide substitution at the -1 position of intron 15 of the BRCA2 gene. This variant, also known as BRCA2 7846-1G>A using alternate nomenclature, has been reported in individuals with peritoneal, breast, and/or pancreatic cancer (Murphy 2002, Walsh 2011, Tung 2016). Additionally, this variant was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies, and co-occurrence with deleterious mutations. BRCA2 c.7618-1G>A 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. Consistent with splicing predictions, functional assays have demonstrated that this variant causes aberrant splicing, resulting in multiple transcripts with a partial deletion of exon 16, with one transcript that also includes a partial deletion of exon 17 (Whiley 2011, Fraile-Bethencourt 2018). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000195358 SCV000695083 pathogenic Hereditary breast and ovarian cancer syndrome 2016-06-10 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7618-1G>A variant involves the alteration of a conserved intronic nucleotide with 5/5 splice prediction tools predicting a significant impact on splicing, which is functionally supported. The variant of interest has not been observed in controls (ExAC, 1000 Gs or ESP) and has been reported in multiple affected individuals via publications. In addition, multiple reputable databases/clinical laboratories cite the variant as "pathogenic." Therefore, the variant of interest has been classified as Pathogenic.
Invitae RCV000195358 SCV000073278 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 15 of the BRCA2 gene. 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 individuals affected with breast cancer (PMID: 21394826, 26681312), and an individual affected with peritoneal carcinoma (PMID: 22006311). This variant is also referred to as c.7846-1G>A and IVS15-1G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38110). Experimental studies have shown that this sequence change produces aberrantly spliced transcripts that are expected to result in a disrupted protein product (PMID: 21394826, 22006311). In addition, multifactorial likelihood analyses developed to assess the clinical relevance of BRCA1 and BRCA2 variants predict that this variant is deleterious (PMID: 21394826, 17924331). 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). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045265 SCV000600761 pathogenic not provided 2016-08-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031692 SCV000054299 pathogenic Breast-ovarian cancer, familial 2 2010-12-09 no assertion criteria provided clinical testing

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