Approach to screening for Lynch syndrome in individuals with colorectal and/or endometrial cancer

CRC: colorectal cancer; IHC: immunohistochemistry; MSI: microsatellite instability; MMR: mismatch repair.
* Germline genetic evaluation may be appropriate in individuals with any one of the following: 1) Family cancer history meeting Amsterdam I or II criteria or revised Bethesda guidelines; 2) >2.5% chance of an MMR gene mutation by prediction models; 3) First-degree relative of those with known MMR/EPCAM gene mutation.
¶ Normal IHC is only approximately 85% sensitive for Lynch syndrome. Consider MSI testing to confirm or rule out deficient MMR.
Δ The presence of MLH1 promoter methylation or BRAF V600E mutation is suggestive of sporadic CRC.
◊ Endometrial tumors are not eligible for BRAF V600E testing, so those with loss of MLH1/PMS2 on IHC should have MLH1 promoter hypermethylation testing.
§ Lynch syndrome should be suspected in individuals with synchronous or metachronous CRC, CRC prior to 50 years of age, multiple Lynch-associated cancers (eg, CRC and endometrial, ovarian, stomach, small intestine, or renal pelvis/ureter), and in cases of familial clustering of Lynch-associated cancers.
¥ Other important considerations include ethnicity, the prevalence of particular genetic founder mutations in some populations, and patient preference.
‡ Refer to UpToDate content on genetic evaluation for Lynch syndrome.
† Individuals with bi-allelic somatic inactivation (by mutation and/or loss of heterozygosity) of MMR genes do not have Lynch syndrome.