ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4675+1G>A (rs80358044)

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Total submissions: 17
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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) RCV000077582 SCV000244367 pathogenic Breast-ovarian cancer, familial 1 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
Invitae RCV000225764 SCV000076636 pathogenic Hereditary breast and ovarian cancer syndrome 2020-03-18 criteria provided, single submitter clinical testing This sequence change affects a consensus donor splice site in intron 14. 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 observed in individuals affected with breast and/or ovarian cancer (PMID: 12491499, 21324516, 23767878, 24884479). In the literature, this variant is also known as IVS15+1G>A and 4794+1G>A. ClinVar contains an entry for this variant (Variation ID: 55256). Experimental studies have shown that this variant results in aberrant splicing (PMID: 21394826, 18489799). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in BRCA1 are known to be pathogenic (PMID: 20104584). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000131822 SCV000186877 pathogenic Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing The c.4675+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 13 of the BRCA1 gene. This mutation has been detected in multiple breast and ovarian cancer families (Zhang S et al. Gynecol. Oncol. 2011 May;121:353-7; Adem C et al. Cancer. 2003 Jan;97:1-11; Maistro S et al. BMC Cancer. 2016 Dec;16:934; Bergthorsson JT et al. J. Med. Genet. 2001 Jun;38(6):361-8; Meisel C et al. Arch. Gynecol. Obstet. 2017 May;295(5):1227-1238). RNA studies have demonstrated that this alteration results in exon skipping of coding exon 13 and/or use of a cryptic donor site resulting in the loss of 11nt of exon 13 (Ambry internal data; Whiley PJ et al. Hum. Mutat. 2011 Jun;32:678-87; Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8; Machackova E et al. BMC Cancer. 2008 May;8:140). Based on multifactorial probability modeling, the posterior probability of this mutation being deleterious was calculated to be 1.00 (Lindor NM et al. Hum. Mutat. 2012 Jan;33:8-21). In addition to the clinical data presented in the literature, 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 pathogenic.
GeneDx RCV000048623 SCV000210184 pathogenic not provided 2019-10-28 criteria provided, single submitter clinical testing Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 11389159, 24667779, 26295337, 29452958, 29907814, 21895635, 21394826, 18712473, 21324516, 21990134, 21965345, 25525159, 12491499, 17924331, 23239986, 18489799, 26913838, 28324225, 27914478, 26976419, 25085752, 24884479, 20104584, 29161300, 30078507, 29446198, 30322717, 29470806, 26848151, 31263571)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048623 SCV000296399 pathogenic not provided 2019-10-30 criteria provided, single submitter clinical testing The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077582 SCV000326016 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000414441 SCV000492461 pathogenic Breast neoplasm criteria provided, single submitter research
Mendelics RCV000225764 SCV000839229 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000762997 SCV000893442 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 1; Pancreatic cancer 4; Fanconi anemia, complementation group S 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131822 SCV000911174 pathogenic Hereditary cancer-predisposing syndrome 2020-02-20 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000048623 SCV001247347 pathogenic not provided 2018-05-01 criteria provided, single submitter clinical testing
Institute of Human Genetics, University of Leipzig Medical Center RCV000077582 SCV001429302 pathogenic Breast-ovarian cancer, familial 1 2020-09-16 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001663924 SCV001877409 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2013-12-01 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000077582 SCV000109385 pathogenic Breast-ovarian cancer, familial 1 2010-07-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077582 SCV000145144 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000225764 SCV000587418 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735555 SCV000863693 likely pathogenic Breast and/or ovarian cancer 2010-10-26 no assertion criteria provided clinical testing

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