ClinVar Miner

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

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Total submissions: 13
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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 2020-01-01 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 The p.I1766S pathogenic mutation (also known as c.5297T>G and5416T>G), located in coding exon 19 of the BRCA1 gene, results from a T to G substitution at nucleotide position 5297. The isoleucine at codon 1766 is replaced by serine, an amino acid with dissimilar properties. This alteration is reported in a woman with ovarian cancer at age 42, a mother with ovarian cancer at age 56 and a maternal aunt with ovarian cancer at age 48; and was not found in her unaffected 51 year-old sister (GuidugliL et al.Breast Cancer Res. Treat. 2011 Jan;125(1):265-72.). Evaluation of this alteration based on co-occurrence, phenotypic analysis and co-segregation estimates 139:1 odds of causality (Easton DF et al.Am. J. Hum. Genet. 2007Nov;81(5):873-83;LindorNM et al.Hum.Mutat. 2012 Jan;33(1):8-21). Analysis of transcriptional activity demonstrates that this alteration results in <40% of wild-type transcription activity in yeast and <20% of wild-type transcription activity in mammalian cells (CarvalhoMA et al.<span class="rangySelectionBoundary" id="selectionBoundary_1437088378806_005387247074395418" style="display:none; line-height:0">Cancer Res. 2007 Feb;67(4):1494-501). In addition, this alteration is demonstrated to inhibit the growth suppression function ofBRCA1in S.cerevisiaeand produces a significant increase in intra- andinterchromosomalrecombination in yeast, in contrast to wild-type (CaligoMA et al. Hum.Mutat. 2009 Jan;30(1):123-33). This alteration is located in theBRCTdomain and is completely buried in the hydrophobic core ofBRCT-C. Structural analysis predicts that the introduction ofserinecreates a buried unsatisfied hydrogen bond that results in a destabilized structure. (CarvalhoMA et al.Cancer Res. 2007 Feb;67(4):1494-501;KarchinR et al.PLoSComput.Biol. 2007 Feb;3(2):e26). This variant was previously reported in the SNPDatabase as rs80357463;however, it was not reported in population-based cohorts in the NHLBI Exome Sequencing Project (ESP) or 1000 Genomes Project databases. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence,p.I1766S is classified as a pathogenic 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 Health, Inc RCV000218342 SCV000683284 pathogenic Hereditary cancer-predisposing syndrome 2017-02-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284552 SCV001470394 pathogenic not provided 2019-11-15 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Located in potentially critical domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
GeneDx RCV001284552 SCV001872674 pathogenic not provided 2021-07-20 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: defective transcriptional activity, reduced cell survival, and protein instability (Glover 2006, Carvalho 2007, Lee 2010, Woods 2016, Findlay 2018); Multifactorial studies suggest this variant is associated with hereditary breast and ovarian cancer (Lindor 2012); Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal or family history of BRCA1-related cancers (Hartmann 2001, Carvalho 2007, Guidugli 2011); Also known as 5416T>G; This variant is associated with the following publications: (PMID: 15235020, 28781887, 25782689, 27272900, 29446198, 15172985, 33087888, 21990134, 20516115, 17305420, 21447777, 20737206, 30209399, 30765603, 17924331, 18680205, 19493677, 27535533, 11698567, 16267036, 18951461, 14534301, 16528612, 17308087)
Research and Development, ARUP Laboratories RCV001659893 SCV001878758 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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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