ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5291T>C (p.Leu1764Pro) (rs80357281)

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Total submissions: 8
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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) RCV000112604 SCV000244395 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 = 0.99
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000112604 SCV000326250 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509995 SCV000607979 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-30 criteria provided, single submitter clinical testing The p.L1764P variant (also known as c.5291T>C), located in coding exon 19 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5291. The leucine at codon 1764 is replaced by proline, an amino acid with similar properties. The Leu1764 residue is deeply buried in the hydrophobic core of the highly conserved BRCT domain and as such, thermodynamic stability assays indicate that p.L1764P has a destabilizing effect (Rowling PJ et al. J Biol Chem. 2010 Jun; 285(26):20080-7). Functional studies including c-DNA complementation, homologous recombination, yeast-based assays, nuclear localization and solubility assays, and transcription activation assays have all demonstrated deficient function (Carvalho MA et al. Cancer Res. 2007 Feb; 67(4):1494-501; Bouwman P et al. Cancer Discov. 2013 Oct; 3(10):1142-55; Lee MS et al. Cancer Res. 2010 Jun 15;70(12):4880-90; Woods NT et al. NPJ Genom Med 2016 Mar;1; Petitalot A et al. Mol. Cancer Res. 2019 01;17(1):54-69). One 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). This alteration is also predicted to be deleterious using a multifactorial likelihood ratio model (Karchin R et al. PLoS Comput Biol. 2007 Feb;3(2):e26). Based in part on the data presented above, this alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Iversen ES Jr et al. Cancer Epidemiol Biomarkers Prev. 2011 Jun;20(6):1078-88; Lindor NM et al. Hum Mutat. 2012 Jan;33(1):8-21). Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588744 SCV000699234 pathogenic Hereditary breast and ovarian cancer syndrome 2017-01-31 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.5291T>C (p.Leu1764Pro) variant located in the BRCT domain (via InterPro) involves the alteration of a conserved nucleotide, which 5/5 in silico tools predict a damaging outcome. Multiple functional studies have been performed that support these predictions. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP) and has been reported in multiple affected individuals via publications and databases. The variant of interest has been indicated to cause fold destabilization. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Counsyl RCV000112604 SCV000786057 pathogenic Breast-ovarian cancer, familial 1 2018-02-14 criteria provided, single submitter clinical testing
Invitae RCV000588744 SCV001578892 pathogenic Hereditary breast and ovarian cancer syndrome 2020-03-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1764 of the BRCA1 protein (p.Leu1764Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 18824701, 29446198, 30257646, 26022348), and has also been observed to segregate with disease in an affected family (Invitae). ClinVar contains an entry for this variant (Variation ID: 55510). This variant has been reported to affect BRCA1 protein function (PMID: 17305420, 27272900, 23867111, 20516115, 17308087, 20378548, 30209399). Based on multifactorial likelihood algorithms using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134). For these reasons, this variant has been classified as Pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000112604 SCV000145441 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112604 SCV001243050 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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