Description
The PMS2 p.Ser46Asn variant was identified in 2 of 370 proband chromosomes (frequency: 0.005) from individuals or families with colorectal cancer (Senter 2008, Everett 2014). The variant was also identified in dbSNP (ID: rs121434629) as "With Pathogenic allele", ClinVar (classified as uncertain significance by InSight; as likely pathogenic by Invitae; and as pathogenic by Mayo Clinic), GeneInsight-COGR, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors database (4x). The variant was not identified in Cosmic, MutDB, or Zhejiang University databases. The variant was identified in control databases in 2 of 240416 chromosomes at a frequency of 0.000008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 2 of 107732 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser46 residue is conserved across mammals and other organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant was reported as a biallelic gene mutation, identified with the PMS2 c.137G>T mutation in an individual with sigmoid adenocarcinoma; the tumour had high microsatellite instability and both the tumour and normal tissue were PMS2-deficient on IHC (Jackson 2008). 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 | | not provided | not provided | not provided | not provided |
