ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.135-1G>T (rs80358158)

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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 RCV000131843 SCV000186898 pathogenic Hereditary cancer-predisposing syndrome 2017-07-11 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
Breast Cancer Information Core (BIC) (BRCA1) RCV000030985 SCV000144430 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Color RCV000131843 SCV000903751 pathogenic Hereditary cancer-predisposing syndrome 2018-01-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000030985 SCV000325042 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000030985 SCV000677633 pathogenic Breast-ovarian cancer, familial 1 2015-11-12 criteria provided, single submitter clinical testing
GeneDx RCV000236913 SCV000292501 pathogenic not provided 2018-05-03 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.135-1G>T or IVS3-1G>T and consists of a G>T nucleotide substitution at the -1 position of intron 3 of the BRCA1 gene. Splicing assays have demonstrated that this variant, also defined as BRCA1 254-1G>T or IVS4-1G>T using alternate nomenclature, results in skipping of exon 4 (previously reported as exon 5) (Tesoriero 2005, Wappenschmidt 2012). This disruption would be predicted to lead to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. BRCA1 c.135-1G>T has been observed in several individuals with a personal or family history suggestive of Hereditary Breast and Ovarian Cancer syndrome (Shattuck-Eidens 1997, Risch 2001, Tesoriero 2005, Rashid 2006, Willems 2008, Spurdle 2010, Zhang 2011). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000047435 SCV000698850 pathogenic Hereditary breast and ovarian cancer syndrome 2016-05-20 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.135-1G>T variant involves the alteration of a conserved intronic nucleotide located at a canonical splice site. Mutation taster predicts a damaging outcome for this variant along with 5/5 in silico splice site prediction algorithms predicting the loss of the splice acceptor site. These predictions were confirmed by Tesoriero_HM_2005 which demonstrated the variant to result in exon skipping that creates an in-frame deletion of 26 amino acids from exon 5. The variant was found in 1/111484 control chromosomes at a frequency of 0.000009, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). It was reported in several HBOC patients and in at least one HBOC family it co-segregated with the disease (Tesoriero_HM_2005). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as Pathogenic. Taken together, this variant is classified as a Pathogenic.
Invitae RCV000047435 SCV000075448 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 3 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in a disrupted protein product. Loss-of -function variants in BRCA1 are known to be pathogenic. This particular variant has been reported in individuals with a personal or family history breast cancer (PMID: 9333265, 11179017, 16211554, 18445692, 20020529, 26187060). This variant is also known as IVS4-1G>T and IVS3-1G>T in the literature. Experimental studies have shown that this splice acceptor change results in an in-frame deletion of exon 4, previously reported as exon 5 (PMID: 16211554, 24212087). Mutifactorial likelihood analysis incorporating segregation data in families and pathological features of the tumors suggests that this variant is disease-associated (PMID: 20020529). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000236913 SCV000296367 pathogenic not provided 2015-07-17 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000047435 SCV000587018 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000030985 SCV000053577 pathogenic Breast-ovarian cancer, familial 1 2012-05-21 no assertion criteria provided clinical testing

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