Nicolaides et al. (1994) identified a germline deletion in the PMS2 gene in a patient with a family history of HNPCC. A second deletion was found in the patient's tumor sample. The tumor from this patient exhibited microsatellite ... Nicolaides et al. (1994) identified a germline deletion in the PMS2 gene in a patient with a family history of HNPCC. A second deletion was found in the patient's tumor sample. The tumor from this patient exhibited microsatellite instability. To examine the contribution of the PMS2 and EXO1 (606063) genes to the HNPCC disease phenotype, Thompson et al. (2004) studied 21 families negative for mutations in MSH2 (609309) and MLH1 (3120436) that fulfilled the Amsterdam diagnostic criteria. They found that mutation in PMS2 accounts for only a small proportion of HNPCC families. Worthley et al. (2005) tested a cohort of 80 patients with features suggestive of HNPCC for evidence of defective mismatch repair and exclusive loss of expression of the PMS2 gene in the tumor. They identified a family with HNPCC due to autosomal dominant inheritance of a loss-of-function mutation in the PMS2 gene and stated that this was the first description of such a kindred. The proband had been diagnosed with cancer of the transverse colon at 49 years of age. Two years later he developed and subsequently died of metastatic esophageal adenocarcinoma. His mother developed endometrial cancer at 60 years of age and carcinoma of the cecum at age 80 years. His maternal grandfather and great-uncle developed colorectal cancer at 66 and 45 years of age, respectively. The brother of the proband had 2 sessile polyps removed from the sigmoid colon, 1 at age 47 and the other at age 49. A maternal uncle died of metastatic squamous cell carcinoma of the esophagus, and his daughter developed breast cancer at the age of 25 years. Hendriks et al. (2006) summarized the phenotype of 7 families with colorectal cancer and a truncating mutation in the PMS2 gene. Although only 3 of the 7 families fulfilled the Amsterdam criteria, in 6 of the 7 families, the pattern of inheritance appeared to be autosomal dominant. The most frequently observed cancer in proven mutation carriers was colorectal carcinoma, followed by endometrial carcinoma and ovarian carcinoma. The mean age at diagnosis was 52 years, approximately 7 to 8 years higher than the mean age of diagnosis observed in families associated with MLH1 and MSH2 mutations. Hendriks et al. (2006) hypothesized that the attenuated phenotype of families with PMS2 mutations may be explained by the fact that in the absence of PMS2, a functional MLH1 and MLH3 (604395) heterodimeric protein can be formed that is able to repair DNA mismatches. In families with MLH1 or MSH2 gene defects, no alternative heterodimers can be created, with consequently a complete inactivation of the mismatch repair system with massive microsatellite instability and a higher risk of cancer.
Among 12 presumably unrelated probands with HNPCC in whom Clendenning et al. (2008) identified a heterozygous insertion/deletion mutation in the PMS2 gene (600259.0015), family history suggested reduced penetrance. Mean age at diagnosis among probands was 52 years. Haplotype ... Among 12 presumably unrelated probands with HNPCC in whom Clendenning et al. (2008) identified a heterozygous insertion/deletion mutation in the PMS2 gene (600259.0015), family history suggested reduced penetrance. Mean age at diagnosis among probands was 52 years. Haplotype analysis indicated a common founder, and the age of the mutation was estimated at 1,625 years, suggesting that this indel mutation arose sometime during the first millennium. The mutation was enriched in patients of British and Swedish ancestry.