See Table A. Genes and Databases for chromosome locus and protein.

Data obtained from universal Lynch syndrome screening for colorectal and endometrial cancers

See Molecular Genetics for information on variants detected in this gene.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants. Detection of exon or whole-gene deletions/duplications require specific sequencing data analysis or use of alternative molecular methods (see footnote 7). For issues to consider in interpretation of sequence analysis results, click here.

Smith et al [2016], van der Klift et al [2016], Yurgelun et al [2017]

Alteration of the proportions may occur in populations with over-representation of specific founder variants.

Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include specific data analysis of gene panels, quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.

Constitutional inactivation of MLH1 by methylation, along with somatic loss of heterozygosity of the functional allele, has been reported to be a rare cause of Lynch syndrome. Such cases are not detectable by either sequence analysis or deletion/duplication analysis of MLH1 (see Molecular Genetics).

Due to the high level of homology between PMS2 and pseudogenes, testing and interpretation of findings in this gene are difficult. A laboratory that adheres to ACMG guidelines for analysis of PMS2 and that has expertise in testing this gene should be selected when a PMS2 pathogenic variant is suspected in a family [Hegde et al 2014]. Long-range PCR, cDNA sequence analysis, and other strategies have been devised to analyze PMS2 [Li et al 2015a, Jansen et al 2020].

Methods to sequence and identify large rearrangements in PMS2 have been developed and improved over time, making it difficult to determine the proportion of pathogenic variants detected by each method in an affected population. Variants detectable by sequence analysis appear to be more common; however, large rearrangements may comprise 20%-50% of pathogenic variants in this gene [van der Klift et al 2010, Vaughn et al 2010, Smith et al 2016, van der Klift et al 2016].

Although EPCAM is not a mismatch repair gene, recurrent germline deletions of the 3' region result in silencing of the adjacent downstream MSH2 by hypermethylation [Niessen et al 2009, Goel et al 2011, Kuiper et al 2011].

Germline deletions of EPCAM result in silencing of the adjacent MSH2 allele by hypermethylation. The adjacent MSH2 allele itself is not mutated (see Molecular Pathogenesis). Sequence analysis of EPCAM without deletion analysis is not appropriate for diagnosis of Lynch syndrome; methods for the detection of large rearrangements should be used (see footnote 7).