ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.1240G>T (p.Asp414Tyr) (rs370752614)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000586084 SCV000149563 uncertain significance not provided 2018-10-17 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.1240G>T at the cDNA level, p.Asp414Tyr (D414Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAC>TAC). This variant, has been reported in at least one individual with pancreatic cancer, who also carried a pathogenic variant in CDKN2A (Yang 2016). Although this variant was observed in large population cohorts, data in this region of PMS2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant 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 Asp414Tyr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000123073 SCV000166368 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 414 of the PMS2 protein (p.Asp414Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been observed in individuals with PMS2-related disease. ClinVar contains an entry for this variant (Variation ID: 127757). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV000217417 SCV000273974 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000217417 SCV000691003 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855654 SCV000697286 uncertain significance not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: PMS2 c.1240G>T (p.Asp414Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 245872 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1240G>T has been reported in the literature in one individual affected with pancreatic cancer, who also carried a pathogenic variant in CDKN2A (co-occurring variant was not specified) (Yang 2016). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All of these laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
True Health Diagnostics RCV000217417 SCV000805281 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-09 no assertion criteria provided clinical testing

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