ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.197T>C (p.Ile66Thr) (rs769554577)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165451 SCV000216181 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000197855 SCV000254610 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-20 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with threonine at codon 66 of the PMS2 protein (p.Ile66Thr). The isoleucine residue is moderately conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs769554577, ExAC 0.01%). This variant has been reported in an individual affected with colorectal cancer (PMID: 27435373). This variant has also been observed on the opposite chromosome (in trans) from a pathogenic variant in PMS2 in an individual affected with ovarian and breast cancer (Invitae). Considering that biallelic pathogenic variants are expected to be found in an individual affected with constitutional mismatch repair-deficiency (CMMR-D), this evidence indicates that this variant is not a primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 185939). An experimental study has shown that this missense change partially decreases PMS2 mismatch repair activity in vitro (PMID: 27435373). 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.
GeneDx RCV000759917 SCV000279266 uncertain significance not provided 2018-08-22 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.197T>C at the cDNA level, p.Ile66Thr (I66T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATT>ACT). This variant has been observed in at least one patient with colorectal cancer and was demonstrated to have proficient mismatch repair efficiency in an in vitro assay (van der Klift 2016). PMS2 Ile66Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in 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 Ile66Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165451 SCV000686172 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-01 criteria provided, single submitter clinical testing
Counsyl RCV000662452 SCV000784925 uncertain significance Hereditary nonpolyposis colorectal cancer type 4 2017-02-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759917 SCV000889615 uncertain significance not provided 2018-06-05 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000759917 SCV001155038 uncertain significance not provided 2018-01-01 criteria provided, single submitter clinical testing

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