ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5144T>C (p.Leu1715Ser) (rs1064793634)

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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 RCV000570188 SCV000666032 likely benign Hereditary cancer-predisposing syndrome 2018-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Color RCV000570188 SCV000910126 likely benign Hereditary cancer-predisposing syndrome 2017-06-06 criteria provided, single submitter clinical testing
GeneDx RCV000587158 SCV000567138 uncertain significance not provided 2017-01-10 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5144T>C at the cDNA level, p.Leu1715Ser (L1715S) at the protein level, and results in the change of a Leucine to a Serine (TTG>TCG). Using alternate nomenclature, this variant would be defined as BRCA2 5372T>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1715Ser 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 Leu1715Ser occurs at a position that is not conserved and is located within the binding domains of RAD51 and POLH (Roy 2012, Buisson 2014)). 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 Leu1715Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587158 SCV000694831 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The BRCA2 variant, c.5144T>C (p.Leu1715Ser) causes a missense change involving a non-conserved nucleotide with 3/4 in-silico tools (SNPs&GO not captured here due to low reliability index) predicting a "benign" outcome, although theses predictions have yet to be functionally assessed. The variant of interest has not been observed in controls (ExAC, 1000 Gs, or ESP), nor has it been, to our knowledge, reported in affected individuals via publications or clinical diagnostic laboratories. A reputable database (believed to be an LCA sample) reports the variant to co-occur with a known BRCA2 pathogenic variant, c.658_659delGT. Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as a VUS-possibly benign until additional information becomes available.
Invitae RCV000637698 SCV000759169 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 1715 of the BRCA2 protein (p.Leu1715Ser). The leucine residue is weakly conserved and there is a large physicochemical difference between leucine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 419381). 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 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 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587158 SCV000887841 uncertain significance not provided 2017-11-15 criteria provided, single submitter clinical testing

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