ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4241T>C (p.Leu1414Pro) (rs878854951)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000231409 SCV000289797 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-10-19 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 1414 of the BRCA1 protein (p.Leu1414Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 240801). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000305147 SCV000329129 uncertain significance not provided 2016-08-31 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4241T>C at the cDNA level, p.Leu1414Pro (L1414P) at the protein level, and results in the change of a Leucine to a Proline (CTA>CCA). Using alternate nomenclature, this variant would be defined as BRCA1 4360T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Leu1414Pro was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting 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 Leu1414Pro occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the SCD domain, within the coiled-coil region and in a region known to interact with multiple other proteins (Narod 2004, Sy 2009, Clark 2012, Paul 2014). 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 Leu1414Pro is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568318 SCV000665817 uncertain significance Hereditary cancer-predisposing syndrome 2016-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence

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