ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1360_1361delinsTC (p.Leu454Ser) (rs587778615)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000223434 SCV000273649 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000121836 SCV000569647 uncertain significance not specified 2016-11-23 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1360_1361delCTinsTC at the cDNA level and p.Leu454Ser (L454S) at the protein level. The normal sequence, with the bases that are deleted and inserted in brackets, is TATG[delCT][insTC]GTCT. This in-frame deletion and insertion occurs on the same allele (in cis) and results in the missense change of a Leucine to a Serine (CTG>TCG). PMS2 c.1360_1361delCTinsTC was identified in 1/681 healthy individuals undergoing whole genome sequencing (Bodian 2014); of note, the participants in this study were younger than 50 years old, thus the unaffected status of this individual may not be significant. Neither PMS2 c.1360_1361delCTinsTC nor PMS2 Leu454Ser (by this or an alternate nucleotide change) was 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 Leucine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. PMS2 Leu454Ser occurs at a position that is not conserved and is not located in a known functional domain (Guarne 2001, Fukui 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether PMS2 Leu454Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000539351 SCV000625517 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces leucine with serine at codon 454 of the PMS2 protein (p.Leu454Ser). 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 PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 135062). 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 RCV000759196 SCV000888390 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing
Color RCV000223434 SCV000913975 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000121836 SCV000920022 uncertain significance not specified 2017-10-27 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.1360_1361delinsTC (p.Leu454delinsSer) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tool predicts a benign outcome for this variant. This variant was found in 1/246258 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; 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.
ITMI RCV000121836 SCV000086034 not provided not specified 2013-09-19 no assertion provided reference population
True Health Diagnostics RCV000223434 SCV000788101 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 no assertion criteria provided clinical testing

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