Lynch Syndrome via the PMS2 Gene

Lynch syndrome (OMIM 120435), also called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited cancer syndrome caused by germline variants in DNA mismatch repair (MMR) genes. MMR genes are responsible for repairing small sequence errors, or mismatches, during DNA replication. Variants in a single mismatch repair gene can cause widespread genomic instability characterized by the expansion or contraction of short tandem repeat sequences (or microsatellites) (reviewed by Grady and Carethers in Gastroenterology 135:1079-1099, 2008). This phenomenon of microsatellite instability (MSI) leads to somatic variants in oncogenes or tumor suppressor genes, including TGFBR2 and NF1 among others (Wang et al. Hum Genet 112:117-123, 2003). As a result, Lynch syndrome is marked by early onset and high lifetime risk of cancer, particularly in the right colon but also in the endometrium, ovary, stomach, bile duct, kidney, bladder, ureter, and brain (Jang and Chung Gut and Liver 4:151-160, 2010). Clinical hallmarks of Lynch syndrome, as delineated by the Amsterdam criteria, include heritable colorectal (type I) or extracolonic (type II) cancer, present in at least three relatives over at least two consecutive generations, with an onset of cancer before the age of 50 in at least one case, and pathological MSI within tumors (Vasen et al. Gastroenterology 116:1453-1456, 1999).

Lynch syndrome is an autosomal dominant disease caused by germline variants in one of five described MMR genes: MLH1, MSH2, MSH6, PMS2 and EPCAM (Idos and Valle. 2021. PubMed ID: 20301390). To date, ~100 pathogenic variations have been reported in the PMS2 gene (OMIM 600258; Human Gene Mutation Database, www.hgmd.cf.ac.uk). While heterozygous germline variants in PMS2 are known to cause Lynch syndrome, biallelic germline PMS2 variants have been identified in patients with constitutive mismatch repair deficiency (CMMR-D) (Wimmer and Etzler Hum Genet 124:105-122, 2008). CMMR-D is characterized by childhood malignancies, mainly hematological and/or neurological, and neurofibromatosis-like café au lait spots.

A variant in PMS2 is detected in 1-2% of Lynch patients (Peltomaki et al. Dis Markers 20:269-276, 2004) and ~50% of CMMR-D patients (Wimmer and Etzler Hum Genet 124:105-122, 2008).

This test provides full coverage of all coding exons of the PMS2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.

DNA analysis of the PMS2 gene is complicated due to the presence of several pseudogenes. One particular pseudogene, PMS2CL, has high sequence similarity to PMS2 exons 11 to 15 (Blount et al. 2018. PubMed ID: 29286535). Next-generation sequencing (NGS) based copy number variant (CNV) analysis can detect deletions and duplications involving exons 1 to 10 of PMS2 but has less sensitivity for exons 11 through 15. Multiplex Ligation-dependent probe amplification (MLPA) can detect deletions and duplications involving PMS2 exons 1 to 15. Of note, PMS2 MLPA is included in this test.