ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7977-1G>C (rs81002874)

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Total submissions: 14
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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) RCV000031714 SCV001161565 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 = 1
Invitae RCV000045368 SCV000073381 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 17. 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 the literature in individuals with prostate, ovarian, and breast cancer (PMID: 12474142, 22006311, 16211554, 23479189). This variant is also known as IVS17-1G>C or 8205-1G>C in the literature. ClinVar contains an entry for this variant (Variation ID: 38132). An experimental study has shown that this variant greatly induced the expression of two naturally occurring transcript isoforms with a skipping of exons 17-18 and exon 18 in RT-PCR and cDNA sequence analysis using patient-derived RNA (PMID: 16211554). A skipping of exon 18 was also confirmed in a separate experimental study (PMID: 22006311). Both aberrant transcripts are expected to result in a frameshift and create premature stop signals in mRNA of the BRCA2 gene. Mutifactorial likelihood analysis incorporating segregation data in families and pathological features of the tumors suggests that this is a disease-associated variant (PMID: 20020529). 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.
Ambry Genetics RCV000162588 SCV000213004 pathogenic Hereditary cancer-predisposing syndrome 2018-03-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031714 SCV000327781 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031714 SCV000488695 pathogenic Breast-ovarian cancer, familial 2 2016-05-24 criteria provided, single submitter clinical testing
GeneDx RCV000486971 SCV000568489 pathogenic not provided 2017-08-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7977-1G>C or IVS17-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 17 of the BRCA2 gene. Using alternate nomenclature, this variant has previously been published as BRCA2 8205-1G>C. 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 been reported to lead to the production of two aberrant transcripts, one containing a deletion of exon 18 and the other containing a deletion of both exon 17 and 18 (Tesoriero 2005) and has been observed in multiple families with a phenotype consistent with Hereditary Breast and Ovarian Cancer (Walsh 2011, de Juan Jimenez 2013). In addition, this variant was strongly predicted by Spurdle et al. (2010) to be pathogenic based on tumor pathology, clinical histories and family studies. Based on the current evidence, we consider this variant to be pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000031714 SCV000575741 pathogenic Breast-ovarian cancer, familial 2 2015-10-22 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507368 SCV000602775 pathogenic not specified 2016-02-17 criteria provided, single submitter clinical testing
Color RCV000162588 SCV000683926 pathogenic Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000486971 SCV000889145 pathogenic not provided 2016-04-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000045368 SCV000919024 pathogenic Hereditary breast and ovarian cancer syndrome 2018-01-15 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7977-1G>C variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict a loss of normal splicing. Functional studies confirm this prediction, with a minigene assays showing several types of aberrant transcripts that exclude exon 18 in its entirety or as an exon 18 derivative, and no canonical transcript (Fraile-Bethencourt_2017). This variant was found in 2/275554 control chromosomes at a frequency of 0.0000073 in gnomAD (with low confidence), which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has been identified in patients affected with breast, ovarian, and prostate cancer (Jimenez_2013, Snape_2012, Walsh_2011, Pritzlaff_2017, Edwards_2003). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031714 SCV000054321 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031714 SCV000147237 pathogenic Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045368 SCV000587925 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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