Description
The PMS2 c.2249G>A, p.(Gly750Asp) variant was identified in the literature in 7 individuals or families with CMMRD, colorectal, ovarian, or breast cancer and was seen in 1 healthy individual (Senter 2008, Bodo 2015, Lavoine 2015, Goodenberger 2016, Shuen 2019, Bono 2021). The variant was also identified in ClinVar (classified as uncertain significance by 2 submitters; as likely pathogenic by Labcorp and 8 other submitters; and as pathogenic by GeneDx and Ambry Genetics). The variant was identified in controls in 27 of 1,603,354 chromosomes (2 homozygous) at a frequency of 0.00002 (Genome Aggregation Database Nov 1 2023 v4.0.0). The variant was observed in trans with pathogenic PMS2 variants in 3 individuals with CMMRD, increasing the likelihood that this c.2249G>A variant has clinical significance (Senter 2008, Lavoine 2015, Bodo 2015). Additionally, the variant was identified in 1 individual with MSI-high colon tumour and confirmed loss of PMS2 expression (Goodenberger 2016). In functional studies, the variant was demonstrated to reduce mismatch repair activity (Drost 2013, Shuen 2019). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | unknown | yes | not provided | not provided | not provided | | 0 | not provided | not provided | not provided |
