Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV001386402 | SCV001586596 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2020-09-17 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in PMS2 are known to be pathogenic (PMID: 21376568, 24362816). A different variant (c.543del) causing the same protein effect (p.Tyr181*) has been observed homozygous in individual(s) with constitutional mismatch repair deficiency syndrome (PMID: 16507833, 30478739). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr181*) in the PMS2 gene. It is expected to result in an absent or disrupted protein product. |
| Laboratory for Molecular Medicine, |
RCV004017829 | SCV004848715 | pathogenic | Lynch syndrome | 2022-06-30 | criteria provided, single submitter | clinical testing | The p.Tyr181X variant has not been previously reported in individuals with PMS2-related malignancies and was absent from large population studies. This nonsense variant leads to a premature termination codon at position 181, which is predicted to lead to a truncated or absent protein. A different variant at the same position also results in a nonsesne variant (c.543delT, p.Tyr181X), and was reported in two individuals with constitutional mismatch repair deficiency (CMMRD) syndrome, one of whom was homozygous and the other was compound heterozyogous with a pathogenic variant (De Vos 2004 PMID: 15077197, Baig 2019 PMID: 30478739). The variant segregated in 4 affected siblings across the two families. Heterozygous family members in the two studies were not reported to have malignancy which is consistent with previous findings of a lower penetrance of monoallelic carriers of PMS2 mutations compared to other MMR genes. Loss of function of the PMS2 gene is an established disease mechanism in autosomal recessive and autosomal dominant Lynch syndrome. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive constitutional mismatch repair deficiency (CMMRD) syndrome. ACMG/AMP Criteria applied: PVS1, PM5, PM2_Supporting. |