ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.398C>T (p.Thr133Ile) (rs1064794097)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000571869 SCV000663562 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-19 criteria provided, single submitter clinical testing Insufficient evidence
Invitae RCV000630025 SCV000750981 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 133 of the PMS2 protein (p.Thr133Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 480373). 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: "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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000756561 SCV000884402 uncertain significance not provided 2017-11-03 criteria provided, single submitter clinical testing The PMS2 c.398C>T; p.Thr133Ile variant is published in the medical literature in at least one individual with endometrial cancer (Ring 2016). The variant is not listed in gene-specific databases, in the ClinVar database, in the dbSNP variant database, or in the general population-based databases (Exome Variant Server, Genome Aggregation Database). The threonine at this position is moderately conserved across species, but computational algorithms do not reach a consensus as to the effect of this variant on the protein (PolyPhen2: Probably Damaging, SIFT: Tolerated, AlignGCGD: C0, Tolerated). Considering available information, the clinical significance of this variant cannot be determined with certainty. References: Ring KL et al. Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod Pathol. 2016 Nov;29(11):1381-1389.

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