ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5297T>G (p.Ile1766Ser) (rs80357463)

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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) RCV000031237 SCV000244396 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 RCV000048915 SCV000076928 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-16 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with serine at codon 1766 of the BRCA1 protein (p.Ile1766Ser). The isoleucine residue is highly conserved and there is a large physicochemical difference between isoleucine and serine. This variant is not present in population databases (rs80357463, ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 20737206, 17308087). ClinVar contains an entry for this variant (Variation ID: 37656). Experimental studies have shown that this missense change affects BRCA1 peptide binding specificity, protease sensitivity and transcriptional activity (PMID: 17305420, 20516115, 17308087, 16528612, 14534301). It also inhibits growth suppression in an in vitro assay (PMID: 19493677, 18680205). In addition, multifactorial likelihood analyses developed to assess the clinical relevance of BRCA1 variants predict that this variant is deleterious (PMID: 21990134, 17924331, 27272900). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000218342 SCV000277074 pathogenic Hereditary cancer-predisposing syndrome 2015-07-17 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other strong data supporting pathogenic classification;Deficient protein function in appropriate functional assay(s);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031237 SCV000326252 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color RCV000218342 SCV000683284 pathogenic Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000048915 SCV001361731 pathogenic Hereditary breast and ovarian cancer syndrome 2019-04-17 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5297T>G (p.Ile1766Ser) results in a non-conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251320 control chromosomes (gnomAD). c.5297T>G has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Rebbeck_2018, Caligo_2009, Judkins_2005, Easton_2007). These data indicate that the variant is likely to be associated with disease. Experimental evidence evaluating an impact on protein function from multiple studies demonstrated the variant of interest to inhibit growth suppression and affect homologous recombination and to have <10% transcriptional activity compared to the wild-type (Thouvenot_2016, Caligo_2009, Carvalho_2007). Five ClinVar submissions from clinical diagnostic laboratories and an expert panel (ENIGMA) (evaluation after 2014) cite the variant four times as pathogenic and once as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Sharing Clinical Reports Project (SCRP) RCV000031237 SCV000053838 pathogenic Breast-ovarian cancer, familial 1 2010-04-09 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031237 SCV000145442 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000048915 SCV000587489 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Brotman Baty Institute,University of Washington RCV000031237 SCV001242585 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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