ClinVar Miner

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

dbSNP: rs1064794097
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Total submissions: 4
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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 2023-08-01 criteria provided, single submitter clinical testing The p.T133I variant (also known as c.398C>T), located in coding exon 5 of the PMS2 gene, results from a C to T substitution at nucleotide position 398. The threonine at codon 133 is replaced by isoleucine, an amino acid with similar properties. This alteration has been previously detected in a cohort of 381 unselected endometrial cancer patients who underwent multi-gene panel testing (Ring KL et al. Mod Pathol, 2016 11;29:1381-1389). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000630025 SCV000750981 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-10-22 criteria provided, single submitter clinical testing This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 133 of the PMS2 protein (p.Thr133Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 480373). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PMS2 protein function. 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.
All of Us Research Program, National Institutes of Health RCV004000897 SCV004836255 uncertain significance Lynch syndrome 2023-12-13 criteria provided, single submitter clinical testing This missense variant replaces threonine with isoleucine at codon 133 of the PMS2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in an individual affected with endometrial cancer (PMID: 27443514). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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