ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5074+1G>T

dbSNP: rs80358053
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Total submissions: 10
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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) RCV000031211 SCV001161633 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 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 = 0.998992
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031211 SCV000326133 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482341 SCV000568399 pathogenic not provided 2016-08-02 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5074+1G>T or IVS16+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 16 of the BRCA1 gene. Using alternate nomenclature, this variant has previously been published as BRCA1 5193+1G>T and IVS17+1G>T. This variant destroys a canonical splice donor 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 in multiple individuals with a personal and/or family history consistent with Hereditary Breast and Ovarian Cancer (Choi 2004, Kang 2015, Gonzalez-Rivera 2016, Seifert 2016). Brose et al. (2004) performed RT-PCR studies that revealed that this variant produces a truncated protein product. In addition, Steffensen et. al. (2014) used a mingene assay to further evaluate the splicing defect caused by this variant and two aberrant transcripts were observed, both of which are expected to result in a truncated protein product. Based on the current evidence, we consider this variant to be pathogenic.
Color Health, Inc RCV000772123 SCV000905198 pathogenic Hereditary cancer-predisposing syndrome 2016-01-27 criteria provided, single submitter clinical testing
Invitae RCV000496776 SCV001585897 pathogenic Hereditary breast ovarian cancer syndrome 2020-02-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 16 of the BRCA1 gene. It is expected to disrupt RNA 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 with breast and/or ovarian cancer (PMID: 15117986, 22752604, 29446198, 30078507). This variant is also known as IVS17+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 37630). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 15345110, 30209399). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496776 SCV001983628 pathogenic Hereditary breast ovarian cancer syndrome 2021-09-20 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5074+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: Three predict the variant abolishes a 5' splicing donor site. Three predict the variant abolishes a 3' acceptor site. In a functional study, this variant was reported to lead to inclusion of intronic sequence resulting in early termination of the BRCA1 protein (Brose_2004). The variant was absent in 251352 control chromosomes. c.5074+1G>T has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome (Juwle_2012, Li_2018, Ryu_2019, Cecener_2020, etc). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031211 SCV000053811 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2007-03-20 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031211 SCV000145289 pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 1999-04-12 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496776 SCV000587451 pathogenic Hereditary breast ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000031211 SCV001237535 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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