ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.547+1G>T (rs80358030)

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Total submissions: 9
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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) RCV000112730 SCV001161645 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 = 0.990586
GeneDx RCV000212159 SCV000210076 pathogenic not provided 2017-10-04 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.547+1G>T or IVS7+1G>T and consists of a G>T nucleotide substitution at the +1 position of intron 7 of the BRCA1 gene. Using alternate nomenclature, this variant would be defined as BRCA1 c.666+1G>T or IVS8+1G>T. The 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 observed in at least one individual with familial breast/ovarian cancer (Evans 2003). Based on the current evidence, we consider BRCA1 c.547+1G>T to be pathogenic.
Ambry Genetics RCV000216456 SCV000276215 pathogenic Hereditary cancer-predisposing syndrome 2020-05-19 criteria provided, single submitter clinical testing The c.547+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 6 of the BRCA1 gene. This alteration was previously reported in families with HBOC (Evans DG et al. J. Med. Genet. 2003 Sep; 40(9):e107; Rebbeck TR et al. Hum. Mutat. 2018 May;39:593-620). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). A close match alteration at the same canonical donor site, BRCA2 c.547+2T>A, also causes skipping of coding exon 6 (designated as exon 8 in the literature) which will produce an out-of-frame transcript with a predicted premature stop codon (Pyne MT et al. Mutat. Res. 1999 Aug;406:101-7; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Colombo M et al. PLoS ONE 2013 Feb;8:e57173). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112730 SCV000326326 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000216456 SCV000683322 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-03 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000496454 SCV001360560 pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-11 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.547+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: Five predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246214 control chromosomes (gnomAD). c.547+1G>T has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018, Li_2016, Evans_2003). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (2x) and twice as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000496454 SCV001589393 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-02 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 7 of the BRCA1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is present in population databases (rs80358030, ExAC 0.01%). This variant has been observed in individuals and families affected with breast and/or ovarian cancer (PMID: 12960223, 26534844, 22333603). This variant is also known as c.666+1G>T in the literature. ClinVar contains an entry for this variant (Variation ID: 55590). Based on a multifactorial likelihood algorithm using clinical and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112730 SCV000145613 pathogenic Breast-ovarian cancer, familial 1 2000-06-12 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496454 SCV000587063 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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