ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.257T>C (p.Leu86Pro) (rs572782576)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000564505 SCV000668776 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000564505 SCV000911014 likely benign Hereditary cancer-predisposing syndrome 2017-02-21 criteria provided, single submitter clinical testing
Counsyl RCV000662463 SCV000784944 uncertain significance Breast-ovarian cancer, familial 2 2017-02-14 criteria provided, single submitter clinical testing
GeneDx RCV000766592 SCV000210444 uncertain significance not provided 2017-01-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.257T>C at the cDNA level, p.Leu86Pro (L86P) 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 BRCA2 485T>C. This variant was reported in an individual of Indian ancestry with a personal and/or family history of breast cancer (Juwle 2012). BRCA2 Leu86Pro 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, but was identified in 1/50 healthy Central Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in the study by Bodian et al. were younger than 50 years old, thus the unaffected status of this individual may not be significant. Since Leucine and Proline differ in some properties, this is considered a semi-conservatIve amino acid substitution. BRCA2 Leu86Pro occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on the currently available information, we consider BRCA2 Leu86Pro to be a variant of uncertain significance.
ITMI RCV000120383 SCV000084535 not provided not specified 2013-09-19 no assertion provided reference population
Invitae RCV000234582 SCV000283191 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-04-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with proline at codon 86 of the BRCA2 protein (p.Leu86Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs572782576, ExAC 0.08%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 133742). 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.

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