ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4986+6T>G (rs80358086)

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Total submissions: 16
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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) RCV000077591 SCV001161549 pathogenic Breast-ovarian cancer, familial 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 = 0.999999
Ambry Genetics RCV000131820 SCV000186875 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-03 criteria provided, single submitter clinical testing The c.4986+6T>G intronic variant results from a T to G substitution 6 nucleotides after coding exon 14 in the BRCA1 gene. This alteration has been reported in multiple families with hereditary breast and/or ovarian cancer (Risch HA et al. Am. J. Hum. Genet. 2001 Mar;68:700-10; Schneegans SM et al. Fam. Cancer. 2012 Jun;11:181-8; Schubert S et al. Int. J. Cancer 2019 Jun;144(11):2683-2694; Rebbeck TR et al. Hum. Mutat. 2018 05;39(5):593-620). In one study using patient lymphoblastoid cell lines, it was shown that this alteration results in an unstable, weakly expressed alternate transcript consisting of a 65 base pair intronic insertion with a premature stop codon at residue 1676, along with 13 additional residues encoded by the insertion (Chen X et al. Hum. Mutat. 2006 May;27:427-35). Results from a mini-gene splicing assay demonstrated that the c.4986+6T>G alteration led to out-of-frame retention of 65bp of intron 16 and increased skipping of exon 16 (Steffensen AY et al. Eur. J. Hum. Genet. 2014 Dec;22:1362-8). Another functional study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature 2018 10;562(7726):217-222). Of note, this alteration is also referred to as 5105+6T>G and IVS16+6T>G in the published literature. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000236376 SCV000293234 pathogenic not provided 2015-10-07 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4986+6T>G or IVS15+6T>G and consists of a T>G nucleotide substitution at the +6 position of intron 15 of the BRCA1 gene. Multiple in silico models predict this variant to weaken the nearby natural donor site, and to possibly cause abnormal gene splicing. An RT-PCR study reported that this variant is associated with aberrant splicing, and leads to a 65bp insertion and a predicted stop codon (Chen 2006). This variant, also denoted BRCA1 5105+6T>G and IVS16+6T>G using alternate nomenclature, has been reported in association with breast and ovarian cancer (Risch 2001, Chen 2006, Zhang 2011, Litton 2012, Schneegans 2012). Based on the currently available information, we consider BRCA1 c.4986+6T>G to be a pathogenic variant.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077591 SCV000326086 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131820 SCV000688529 pathogenic Hereditary cancer-predisposing syndrome 2020-02-05 criteria provided, single submitter clinical testing
Counsyl RCV000077591 SCV000785365 likely pathogenic Breast-ovarian cancer, familial 1 2017-07-14 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000769711 SCV000901131 pathogenic Breast and/or ovarian cancer 2017-03-08 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000077591 SCV001434960 pathogenic Breast-ovarian cancer, familial 1 2019-02-05 criteria provided, single submitter clinical testing This c.4986+6T>G variant in the BRCA1 gene has been reported in multiple individuals affected with breast cancer or ovarian cancer (PMID 11179017, 16619214, 21913181, 22160602) and is extremely rare in general population databases. An RT-PCR assay using mRNA derived from an affected individual showed 65bp insertion, which is predicted to introduce a premature translation termination codon (PMID 16619214). Therefore, the c.4986+6T>G variant in the BRCA1 gene is classified as pathogenic.
Invitae RCV000496750 SCV001591918 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-02 criteria provided, single submitter clinical testing This sequence change falls in intron 15 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is present in population databases (rs80358086, ExAC 0.001%). This variant has been observed in individuals with breast and/or ovarian cancer (PMID: 11179017, 16619214, 22160602, 21913181). ClinVar contains an entry for this variant (Variation ID: 55344). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing and/or protein function (PMID: 16619214, 24667779, 30209399). A different variant affecting this nucleotide (c.4986+6T>C) has been determined to be pathogenic (PMID: 10406662, 21324516, 21965345, 21120943, 24729269). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001663972 SCV001877429 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) RCV000077591 SCV000109394 pathogenic Breast-ovarian cancer, familial 1 2012-07-23 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077591 SCV000145239 not provided Breast-ovarian cancer, familial 1 no assertion provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496750 SCV000587439 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353600 SCV000591551 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The c.4986+6T>G variant has been previously reported in the literature in 1 out of 1298 proband chromosomes, in an individual with ovarian cancer (Risch 2001). The variant has also been identified by our laboratory in one family where the variant was demonstrated to segregate with disease in 5 affected family members with breast cancer, suggesting this variant is pathogenic. In the UMD, BIC and LOVD databases, an intronic mutation at the same genomic location but with a different base alteration (IVS16+16 T>C) was described as being a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site. It is listed in the dbSNP database (rs80358086) but no frequency information was provided and so the population frequency could not be assessed. The variant is located in the 5' splice region but does not affect the highly conserved +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In summary, based on above information, this variant is classified as pathogenic.
Brotman Baty Institute,University of Washington RCV000077591 SCV001243881 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Medical Genetics Laboratory, Umraniye Training and Research Hospital,University of Health Sciences RCV001554289 SCV001774877 pathogenic Breast carcinoma 2021-08-08 no assertion criteria provided clinical testing

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