Description
Variant summary: PMS2 c.2521delT (p.Trp841GlyfsX10) results in a premature termination codon in the last exon of the PMS2 mRNA, predicted to cause a truncation and disrupt the last 22 amino acids (Trp841-Asn862) of the PMS2 protein. The variant was absent in 177052 control chromosomes (in gnomAD). However, the variant c.2523G>A (p.Trp841X) has been observed in 64/10632 African alleles in gnomAD, including 3 homozygotes, suggesting loss of the far end of C-terminal of PMS2 protein (the last 22 amino acids Trp841-Asn862) is likely tolerable, although the technology utilized for this dataset does not rule out pseudogene interference and thus this data might not be relied upon. It was shown in an in vitro study that the C-terminal (amino acids 675-850) region of PMS2 is critical for PMS2-MLH1 dimerization , as the interaction was lost for the tested protein fragment truncated at amino acid 825 (Guerrette 1999), suggesting the region between amino acids 825-850 is critical for PMS2-MLH1 interaction. However, from these data the impact of truncation at amino acid 841 cannot be determined for the MLH1 interaction. The variant, c.2521delT, has been reported in the literature in two individuals affected with constitutional mismatch repair deficiency (CMMRD) syndrome. In one case it was found in homozygosity in a 4 years old patient diagnosed with high-grade glioma (Bodo 2015, Maletzki 2017), in the other case it was found in co-occurrence with the pathogenic PMS2 variant (c.2T>A (p.Met1Lys); Machackova 2016). The homozygous patient was from a consanguineous family, where three relatives were affected with Lynch syndrome- or CMMRD-associated cancers on the maternal side (they were diagnosed at the the age 5, 9 and 15 years). In functional studies performed on lymphoblastoid cell lines (LCLs) derived from the patient carrying the variant in homozygosity, MSI (microsatellite instability) and tolerance to methylating agents could be demonstrated (while these changes couldn't be shown in LCLs from MMR-proficient controls, including Lynch syndrome patients; Bodo 2015). In another study, authors demonstrated MSI in the tumor obtained from the homozygous patient (Maletzki 2017). These results suggest that the variant is probably associated with the disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Three classified as likely pathogenic/pathogenic while one classified as VUS. Based on the evidence outlined above, the variant was classified as likely pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
