ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5357T>C (p.Leu1786Pro) (rs398122697)

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Total submissions: 6
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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 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-05-02 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 <0.01%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12938098, 26689913, 29113215). It is also known as 5476C>T in the literature. ClinVar contains an entry for this variant (Variation ID: 91649). Experimental studies have shown that this missense change disrupts BRCA1 homology-directed repair activity in vitro but has little effect on the cellular functions of BRCA1 in a breast cancer cell line (PMID: 26689913, 29113215). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000159852 SCV000591621 uncertain significance not specified 2012-03-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509661 SCV000607969 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,Deficient protein function in appropriate functional assay(s)
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

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