ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1243G>T (p.Val415Leu) (rs138387687)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000465085 SCV000552056 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-06-02 criteria provided, single submitter clinical testing This sequence change replaces valine with leucine at codon 415 of the PMS2 protein (p.Val415Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs138387687, ExAC 0.01%). This variant has not been reported in the literature in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 411079). 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 leucine 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.
GeneDx RCV000587977 SCV000565396 uncertain significance not provided 2017-10-06 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1243G>T at the cDNA level, p.Val415Leu (V415L) at the protein level, and results in the change of a Valine to a Leucine (GTG>TTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. PMS2 Val415Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Valine and Leucine share similar properties, this is considered a conservative amino acid substitution. PMS2 Val415Leu is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether PMS2 Val415Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587977 SCV000697290 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1243G>T (p.Val415Leu) variant involves the alteration of a non-conserved nucleotide. 3/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 2/120354 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Color RCV000772619 SCV000905804 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-17 criteria provided, single submitter clinical testing
Ambry Genetics RCV000772619 SCV001170724 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-11 criteria provided, single submitter clinical testing Insufficient or conflicting evidence

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