ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.647G>T (p.Cys216Phe) (rs730881908)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160882 SCV000211571 uncertain significance not provided 2018-10-23 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.647G>T at the cDNA level, p.Cys216Phe (C216F) at the protein level, and results in the change of a Cysteine to a Phenylalanine (TGC>TTC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. PMS2 Cys216Phe was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the ATPase domain (Guarne 2001). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether PMS2 Cys216Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000574055 SCV000663482 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000574055 SCV000691094 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-21 criteria provided, single submitter clinical testing
Invitae RCV000629988 SCV000750944 uncertain significance Hereditary nonpolyposis colon cancer 2019-12-03 criteria provided, single submitter clinical testing This sequence change replaces cysteine with phenylalanine at codon 216 of the PMS2 protein (p.Cys216Phe). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and phenylalanine. This variant is present in population databases (rs730881908, ExAC 0.003%). This variant has been observed in an individual affected with B-Cell acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 182798). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; 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.
Integrated Genetics/Laboratory Corporation of America RCV000781737 SCV000920024 uncertain significance not specified 2019-08-30 criteria provided, single submitter clinical testing Variant summary: PMS2 c.647G>T (p.Cys216Phe) results in a non-conservative amino acid change located in the N-terminal DNA mismatch repair domain (IPR002099) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251492 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.647G>T has been reported in the literature in i in a child affected with B-Cell Acute Lymphoblastic Leukemia (Zhang_2015). 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. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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