Lynch syndrome and Lynch syndrome mimics: The growing complex landscape of hereditary colon cancer

Table 1 Germline and cancer-specific genetic and epigenetic features for hereditary non-polyposis colorectal cancer conditions

	Lynch syndrome	CMMRD	Lynch-like syndrome	Sporadic MSI CRC and sessile serrated polyps	FCCTX	PPAP	HBOC
Germline mutation	One allele of a MMR gene: MSH2, MLH1, MSH6, PMS2, EPCAM	Both alleles of a MMR gene: MSH2, MLH1, MSH6, PMS2, EPCAM	None	None	RPS20, SEMA4A, HNRNPA0, WIF1, likely others	POLE (L424V) POLD1 (S478N) (other exonuclease domain mutations)	BRCA1 or BRCA2
Somatic mutation	2nd allele of MMR gene	None	Both alleles of a MMR gene	BRAF	Various	2nd allele of POLE, POLD1 and > 100 × somatic mutations (hypermutated) compared with other MSS tumors	2nd allele of BRCA1 or BRCA2
Tumor MMR phenotype	MMR deficient (MSI)	MMR deficient (MSI)	MMR deficient (MSI)	MMR deficient, (MSI)	MMR proficient (MSS)	MMR proficient (MSS)	MMR proficient (MSS)
Epigenetic	Germline deletion in 3’ end of EPCAM leads to Somatic Allele-specific MSH2 methylation in tissues	None reported	None reported	Somatic biallelic promoter methylation for MLH1	None reported	None reported	None reported

MSS: Microsatellite stable; CMMRD: Constitutional mismatch repair-deficiency; FCCTX: Familial colorectal cancer type X; PPAP: Polymerase proofreading associated polyposis syndrome; HBOC: Hereditary breast and ovarian cancer syndrome; MSI: Microsatellite instability; CRC: Colorectal cancer.