ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.74C>T (p.Pro25Leu) (rs876660096)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223256 SCV000277233 uncertain significance Hereditary cancer-predisposing syndrome 2015-07-18 criteria provided, single submitter clinical testing
Invitae RCV000227670 SCV000289843 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-02-05 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 25 of the BRCA1 protein (p.Pro25Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.
GeneDx RCV000236374 SCV000293941 uncertain significance not provided 2016-02-09 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.74C>T at the cDNA level, p.Pro25Leu (P25L) at the protein level, and results in the change of a Proline to a Leucine (CCC>CTC). Using alternate nomenclature, this variant would be defined as BRCA1 193C>T. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Pro25Leu 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 Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Pro25Leu occurs at a position that is conserved across species and is located in the RING finger domain as well as a region known to interact with multiple other proteins (Narod 2004, Paul 2014). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Pro25Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735502 SCV000863640 uncertain significance Breast and/or ovarian cancer 2016-01-28 no assertion criteria provided clinical testing

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