ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4067T>C (p.Leu1356Ser) (rs876660967)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000771388 SCV000903727 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 criteria provided, single submitter clinical testing
GeneDx RCV000759612 SCV000278849 uncertain significance not provided 2015-11-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.4067T>C at the cDNA level, p.Leu1356Ser (L1356S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG) in exon 11. Using legacy nomenclature, this variant would be defined as BRCA2 4295T>C. This variant has not, to our knowledge, been published in the literature as either a mutation or a benign polymorphism. BRCA2 Leu1356Ser 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 Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu1356Ser occurs at a position that is not conserved and is located in the RAD51 binding domain (Roy 2012). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether BRCA2 Leu1356Ser is a pathogenic or a benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000558819 SCV000635331 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-06 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 1356 of the BRCA2 protein (p.Leu1356Ser). The leucine residue is moderately conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 234278). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The serine 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. In summary, this variant is a rare missense change that is not predicted to affect 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000239292 SCV000296528 uncertain significance Breast-ovarian cancer, familial 2 2016-04-15 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759612 SCV000889040 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing

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