ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5357T>C (p.Leu1786Pro)

dbSNP: rs398122697
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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766591 SCV000209896 likely pathogenic not provided 2020-01-10 criteria provided, single submitter clinical testing Observed in individuals with breast and/or ovarian cancer (Meyer 2003, Zhang 2017); Published functional studies support a damaging effect (Lu 2015, Zhang 2017, Findlay 2018, Fernandes 2019); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Also known as 5476T>C; This variant is associated with the following publications: (PMID: 26689913, 10811118, 12938098, 29113215, 28726806, 30765603, 30209399, 18069886, 31825140)
Invitae RCV000465437 SCV000549362 likely pathogenic Hereditary breast ovarian cancer syndrome 2022-12-24 criteria provided, single submitter clinical testing 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. Experimental studies have shown that this missense change affects BRCA1 function (PMID: 26689913, 29113215, 30209399, 30765603). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 30209399) indicates that this missense variant is expected to disrupt BRCA1 function. ClinVar contains an entry for this variant (Variation ID: 91649). This variant is also known as 5476C>T. This missense change has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12938098, 26689913, 29113215, 32803532; Invitae). This variant is present in population databases (rs398122697, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 1786 of the BRCA1 protein (p.Leu1786Pro).
Ambry Genetics RCV000509661 SCV000607969 likely pathogenic Hereditary cancer-predisposing syndrome 2023-04-13 criteria provided, single submitter clinical testing The p.L1786P variant (also known as c.5357T>C), located in coding exon 20 of the BRCA1 gene, results from a T to C substitution at nucleotide position 5357. The leucine at codon 1786 is replaced by proline, an amino acid with similar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts (Meyer P et al. Hum. Mutat. 2003 Sep; 22(3):259; Shao D et al. Cancer Sci, 2020 Feb;111:647-657; Wan Q et al. Fam Cancer, 2021 Apr;20:85-95). This alteration was also found to be non-functional in multiple studies (Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Fernandes VC et al. J Biol Chem, 2019 04;294:5980-5992; Zhang H et al. Oncol Lett, 2017 Nov;14:5839-5844; Findlay GM et al. Nature. 2018 10;562:217-222). Based on internal structural assessment, this alteration results in moderate structural disruption of the BRCT domain (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000766591 SCV001133626 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000509661 SCV001346185 likely pathogenic Hereditary cancer-predisposing syndrome 2021-07-20 criteria provided, single submitter clinical testing This missense variant replaces leucine with proline at codon 1786 of the BRCA1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown the variant protein to be defective in transcriptional activity (PMID: 30765603), homology-directed DNA repair (PMID: 26689913, 32546644) and in a haploid cell proliferation assay (PMID: 30209399). This variant has been reported in individuals and families affected with breast and ovarian cancer (PMID 12938098, 26689913, 29113215, Color internal data). This variant has been identified in 1/251444 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000465437 SCV001429665 likely pathogenic Hereditary breast ovarian cancer syndrome 2019-06-01 criteria provided, single submitter clinical testing Data included in classification: Observed once in 125,722 gnomAD controls. (PM2_sup). Non-functional in SGE haploid BRCA1-assay (Findlay et al. 2018); Lu et al. (2015) homology-directed repair assay PMID: 26689913 (PS3_strong). Variant in BRCT domain (PM1_sup). Data not included in classification: Not observed in 25,773 UK familial cases. UK family 1: Proband was tested in Australia. Molecular report suggests strong segregation with the disease, involving 12 individuals from 5 independent families. Literature: Meyer et al 2003 - PMID: 12938098 (1 family no information about number of individuals). Predicted deleterious by SIFT and MAPP. Predicted benign by Polyphen HumVar and Align GVGD. Additional reports of variant in ClinVar (6), BIC (2) and BRCA1 LOVD (2), UMD(0), HGMD (0). Classified as VUS by Ambry 2017, Gene Dx 2016, Invitae 2018.
Breast Center, Key Laboratory of Carcinogenesis and Translational Research RCV000465437 SCV001430342 uncertain significance Hereditary breast ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000465437 SCV001774681 likely pathogenic Hereditary breast ovarian cancer syndrome 2021-07-12 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.5357T>C (p.Leu1786Pro) results in a non-conservative amino acid change located in the BRCT domain 2 (IPR001357) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes (gnomAD). c.5357T>C has been reported in the literature in individuals affected with breast and/or ovarian cancer (Meyer_2003, Lu_2015, Zhang_2017, Shao_2019). These data indicate that the variant may be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant results in similar levels of cell proliferation and apoptosis as the wild-type in transfected cells (Zhang_2017); however, in several other studies the variant was demonstrated to affect protein function, e.g. resulting in decreased transcriptional activity and defective homology-directed repair(Lu_2015, Findlay_2018, Fernandes_2019, Bouwman_2020). Co-occurrence with another pathogenic variant have been reported (BRCA2 c.2818C>T (p.Gln940X), in an internal LCA sample) providing supporting evidence for a benign role. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as VUS (n=3) or likely pathogenic (n=4). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Baylor Genetics RCV000077166 SCV004211755 likely pathogenic Breast-ovarian cancer, familial, susceptibility to, 1 2021-06-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077166 SCV000108963 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-01-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077166 SCV000145479 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2013-03-25 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000159852 SCV000591621 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The p.Leu1786Pro variant has been reported in the literature in 2 of 251 probands with breast or ovarian cancer (Meyer 2003), but population controls were not included in this study. The p.Leu1786 residue is conserved in mammals but not in lower organisms and computational analyses (SIFT, AlignGVGD) provide inconsistent predictions regarding the impact to the protein and this information is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classfied as a variant of unknown significance.
Brotman Baty Institute, University of Washington RCV000077166 SCV001238226 not provided Breast-ovarian cancer, familial, susceptibility to, 1 no assertion provided in vitro

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