ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4616T>C (p.Leu1539Pro) (rs377629427)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462374 SCV000549372 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1539 of the BRCA1 protein (p.Leu1539Pro). The leucine residue is weakly 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 not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 409342). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The proline amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
GeneDx RCV000478001 SCV000570390 uncertain significance not provided 2016-05-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4616T>C at the cDNA level, p.Leu1539Pro (L1539P) at the protein level, and results in the change of a Leucine to a Proline (CTG>CCG). Using alternate nomenclature, this variant would be defined as BRCA1 4735T>C. Functional analysis using transcriptional assays demonstrated no significant difference between BRCA1 Leu1539Pro and wild-type BRCA1 (Woods 2016). BRCA1 Leu1539Pro was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Leucine and Proline differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Leu1539Pro occurs at a position that is not conserved and is located in within a region known to interact with multiple other proteins (Paul 2014). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Leu1539Pro is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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