Description
The PMS2 p.Ser46Ile variant was identified in 11 of 1466 proband chromosomes (frequency: 0.008) from individuals or families with hereditary breast and ovarian cancer syndrome or Lynch syndrome and was not identified in 2490 control chromosomes from healthy individuals (Bodo 2017, Borras 2013, Clendenning 2006, Senter 2008, Pastrello 2011, Dorschner 2013, Nakagawa 2004). The variant was also identified in dbSNP (ID: rs121434629) as “With Pathogenic, Uncertain significance allele”, ClinVar (classified as pathogenic by GeneDx, Ambry Genetics, Invitae, and 8 other submitters; and as likely pathogenic by InSiGHT expert panel in 2014 and 7 other submitters), COGR (2x), Insight Colon Cancer Gene Variant Database (1x as class 4), Mismatch Repair Genes Variant Database (4x), and Insight Hereditary Tumors Database (25x). The variant was not identified in Cosmic or Zhejiang Colon Cancer Database. The variant was identified in control databases in 48 of 277180 chromosomes at a frequency of 0.0002 (Genome Aggregation Consortium Feb 27, 2017), in the following populations: Latino in 11 of 35326 chromosomes (frequency: 0.0003) and European in 37 of 125388 chromosomes (frequency: 0.0003); it was not identified in the African, Other, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The variant was identified in several cases with CMRD or Turcot syndrome as a biallelic variant with one of the following PMS2 variants: c.1951C>T, c.2174+1G>A, c.804-2A>G, and c.137G>A (Agostini 2005, Herkert 2011, Giunti 2009, Jackson 2008, Senter 2008). The variant is located within the functional domain of histidine kinase-like ATPase, increasing the likelihood that it may have clinical significance. Functional assays have shown that this variant had reduced mismatch repair efficiency (Drost 2013) and resulted in near absence of the PMS2 protein (Auclair 2007). One study suggests that this variant may by a founder mutation in a population of undetermined ancestry (Tomsic et al 2013). This variant has also been identified by our laboratory in two patients affected with Lynch syndrome and PMS2-deficient colon tumours. The p.Ser46 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that this variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as 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 |
