ClinVar Miner

Submissions for variant NM_000535.7(PMS2):c.2444C>T (p.Ser815Leu) (rs587779338)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076859 SCV000108351 likely pathogenic Lynch syndrome 2018-10-18 reviewed by expert panel curation Abrogated MMR activity in 2 independent labs, 4 MSI-H/IHC loss tumors, MAF<0.01, 1 Ams family with 2 non-proband affected carriers.
Ambry Genetics RCV000130249 SCV000185093 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000485694 SCV000565423 likely pathogenic not provided 2018-07-31 criteria provided, single submitter clinical testing This variant is denoted PMS2 c.2444C>T at the cDNA level, p.Ser815Leu (S815L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been reported in the heterozygous state in several patients with Lynch syndrome, with tumors from two such individuals showing absent PMS2 expression on immunohistochemistry (van der Klift 2010, Brea-Fernandez 2014, ten Broeke 2015, van der Klift 2016). PMS2 Ser815Leu has also been observed in the homozygous state in an individual with constitutional mismatch repair deficiency (Suerink 2017). In vitro functional studies have found that PMS2 Ser815Leu results in deficient mismatch repair activity similar to a known pathogenic missense variant, PMS2 Ser46Ile (van der Klift 2016, Gonzalez-Acosta 2017). PMS2 Ser815Leu was not observed in large population cohorts (Lek 2016). This variant is located within the endonuclease domain (Fukui 2011). In silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on the currently available evidence, we consider PMS2 Ser815Leu to be a likely pathogenic variant.
Invitae RCV000525929 SCV000625619 likely pathogenic Hereditary nonpolyposis colon cancer 2018-10-12 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 815 of the PMS2 protein (p.Ser815Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. The frequency data for this variant in the population databases (rs587779338, ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. This variant has been observed in several individuals affected with colorectal cancer or other Lynch syndrome-related tumors (PMID: 23837913, 27435373, 20186688, 26110232, 25512458), and in two individuals with features consistent with constitutional mismatch repair deficiency (CMMRD) (PMID: 28503822, Invitae). This variant was also reported to segregate in a Lynch syndrome family (PMID: 28365877). ClinVar contains an entry for this variant (Variation ID: 91343). Experimental studies have shown that this missense change causes a significant reduction in PMS2 mismatch repair activity in vitro (PMID: 27435373, 28365877). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Fulgent Genetics,Fulgent Genetics RCV000764719 SCV000895854 uncertain significance Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 4 2018-10-31 criteria provided, single submitter clinical testing

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