ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5357T>C (p.Leu1786Pro) (rs398122697)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000766591 SCV000209896 uncertain significance not provided 2016-02-16 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5357T>C at the cDNA level, p.Leu1786Pro (L1786P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). This variant, also denoted BRCA1 5476T>C using alternate nomenclature, was observed in a German family with breast and ovarian cancer, however information regarding ages at diagnosis or who in the family was tested was not provided (Meyer 2003). One functional assay by Lu et al. (2015) found that BRCA1 Leu1786Pro impacted homology-directed repair activity, and loss of the wild-type allele was noted in one breast tumor harboring this variant. BRCA1 Leu1786Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Leu1786Pro occurs at a position that is conserved in mammals and is located in the second BRCT domain and a region known to interact with multiple other proteins (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Leu1786Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000465437 SCV000549362 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-24 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1786 of the BRCA1 protein (p.Leu1786Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs398122697, ExAC 0.002%). This variant has been observed in individual(s) with breast and/or ovarian cancer (PMID: 12938098, 26689913, 29113215, Invitae). This variant is also known as 5476C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 91649). This variant has been reported to affect BRCA1 protein function (PMID: 26689913, 29113215, 30209399, 30765603). 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 RCV000509661 SCV000607969 likely pathogenic Hereditary cancer-predisposing syndrome 2019-09-11 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 (referred to as c.5476T>C) has been reported in one German breast and/or ovarian cancer family (Meyer P et al. Hum. Mutat. 2003 Sep; 22(3):259). This alteration was also found to be non-functional in multiple studies (Lu C et al. Nat Commun. 2015 Dec 22;6:10086; Findlay GM et al. Nature. 2018 10;562:217-222). 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 Health, Inc RCV000509661 SCV001346185 likely pathogenic Hereditary cancer-predisposing syndrome 2019-05-08 criteria provided, single submitter clinical testing
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000465437 SCV001429665 likely pathogenic Hereditary breast and 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 and ovarian cancer syndrome 2020-05-01 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077166 SCV000108963 uncertain significance Breast-ovarian cancer, familial 1 2010-01-16 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077166 SCV000145479 uncertain significance Breast-ovarian cancer, familial 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 1 no assertion provided in vitro

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