ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.697C>T (p.Gln233Ter) (rs587779343)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076881 SCV000108375 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
GeneDx RCV000212848 SCV000149610 pathogenic not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.697C>T at the cDNA level and p.Gln233Ter (Q233X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals with a personal and/or family history consistent with Lynch syndrome (Niessen 2009, van der Klift 2016, Rossi 2017) and is considered pathogenic.
Ambry Genetics RCV000115701 SCV000214344 pathogenic Hereditary cancer-predisposing syndrome 2018-05-17 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000524479 SCV000551989 pathogenic Hereditary nonpolyposis colon cancer 2019-10-14 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln233*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs587779343, ExAC 0.001%). This variant has been observed in individuals affected with Lynch syndrome and suspected Lynch syndrome (PMID: 19132747, 20186688, 26110232, 25512458, 27435373). ClinVar contains an entry for this variant (Variation ID: 91362). Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). For these reasons, this variant has been classified as Pathogenic.
Color RCV000115701 SCV000686226 pathogenic Hereditary cancer-predisposing syndrome 2017-02-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076881 SCV000697377 pathogenic Lynch syndrome 2017-05-05 criteria provided, single submitter clinical testing Variant summary: The PMS2 c.697C>T (p.Gln233X) variant results in a premature termination codon, predicted to cause a truncated or absent PMS2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g., c.735dupG [p.Pro246fsX3], c.823C>T [p.Gln275X], and c.1021delA [p.Arg341fsX15]). One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC at a frequency of 0.0000082 (1/121462 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PMS2 variant (0.0001136). In the literature, patients and families with colorectal cancer and other Lynch syndrome-associated cancers have been identified as carriers of the variant and include supporting molecular data, such as absence of PMS2 in tumor samples (via immunohistochemical staining) and microsatellite instability (Niessen_GCC_2009; van der Klift_HM_2016). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

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