Lynch Syndrome
What it is
Lynch syndrome is the most common hereditary cause of colorectal and endometrial cancer (~1 in 279 people). It results from a germline pathogenic variant in a DNA mismatch-repair (MMR) gene — MLH1, MSH2, MSH6, or PMS2 — or from an EPCAM deletion that silences the neighboring MSH2. Loss of mismatch repair produces microsatellite-instability-high (MSI-H), MMR-deficient tumors.
How it gets found
Universal tumor screening — every colorectal and endometrial cancer is tested for MMR deficiency (IHC for the four proteins, or MSI testing). An abnormal result → germline testing. This catches Lynch that family history alone misses.
Family-history tools the FP can use to prompt referral: Amsterdam II criteria, the revised Bethesda guidelines, or the PREMM5 risk model (a ≥2.5% score prompts genetic evaluation).
The clinical tells: colorectal or endometrial cancer before 50, multiple Lynch-spectrum cancers in one person or lineage (colorectal, endometrial, ovarian, gastric, urothelial, small bowel, sebaceous), or a known MSI-H / MMR-deficient tumor in a relative.
Risk is gene-specific
The gene matters — MLH1/MSH2 (and EPCAM for colorectal) are high-penetrance and early-onset; MSH6/PMS2 are lower-penetrance and later. Lifetime risks below are to age 70 (Prospective Lynch Syndrome Database).
| Gene | Colorectal (by 70) | Endometrial (by 70) | Other spectrum | Onset |
|---|---|---|---|---|
| MLH1 high-penetrance | 44% (female) / 53% (male) by age 70 (Prospective Lynch Syndrome Database) | ~35% by age 70 | ovarian ~11%, gastric ~8%, urinary tract, biliary / pancreatic, brain (glioblastoma — Turcot) | early — mean colorectal onset ~44 years |
| MSH2 high-penetrance | 42% (female) / 46% (male) by age 70 (Prospective Lynch Syndrome Database) | ~46% by age 70 (highest of the MMR genes) | ovarian ~17%, gastric ~16%, urinary tract / urothelial (notably elevated), small bowel, brain ~2%, sebaceous tumors (Muir-Torre) | early — mean colorectal onset ~44 years |
| MSH6 lower-penetrance | 20% (female) / 12% (male) by age 70 (Prospective Lynch Syndrome Database) | ~41% by age 70 (endometrial-predominant) | ovarian ~11%, gastric ~10% | later — colorectal onset commonly ~42–69 years |
| PMS2 lower-penetrance | ~3% by age 70 (Prospective Lynch Syndrome Database) — the lowest-penetrance MMR gene | ~12–13% by age 70 | low extracolonic risk overall | late — colorectal onset commonly ~61–66 years |
| EPCAM high-penetrance | Up to ~75% cumulative lifetime (Kempers 2011 — no PLSD data exist for EPCAM); colorectal risk is similar to MSH2/MLH1, not higher. | lower for isolated 3' deletions; MSH2-like if the deletion extends into MSH2 | lower extracolonic risk than MSH2 | MSH2-like for colorectal |
Note: Highest-risk pair with MSH2; early-onset colorectal cancer drives surveillance starting at 20–25.
What to tell the patient: Counsel that colonoscopy every 1–2 years is the single most important intervention and that it starts young. Ensure they understand this is lifelong, not a one-time test.
GeneReviews: Lynch Syndrome (Idos & Valle, 2021); Prospective Lynch Syndrome Database (Møller et al.).
Note: Broadest extracolonic spectrum: the urothelial and Muir-Torre (sebaceous) associations are strongest here.
What to tell the patient: Same colonoscopy message as MLH1, plus flag the wider cancer spectrum — urinary symptoms and new sebaceous skin lesions warrant attention, and the endometrial/ovarian risk makes the risk-reducing surgery conversation relevant.
GeneReviews: Lynch Syndrome (Idos & Valle, 2021); Prospective Lynch Syndrome Database (Møller et al.).
Note: Endometrial-predominant, lower and later colorectal risk. Do not under-counsel the endometrial risk because the colorectal number is lower.
What to tell the patient: Frame it as endometrial-first: the gyn cancer risk is near the high-penetrance genes even though colorectal risk is lower. Colonoscopy still indicated, and the risk-reducing hysterectomy discussion is central.
GeneReviews: Lynch Syndrome (Idos & Valle, 2021); Prospective Lynch Syndrome Database (Møller et al.).
Note: Lowest penetrance — but the 3% figure is the low end of a contested range, and colonoscopy is still recommended, just later: typically starting ~35 (vs 20–25 for MLH1/MSH2). Do not dismiss the result.
What to tell the patient: Reassure proportionately: the absolute risks are much lower than MLH1/MSH2, but surveillance is still warranted. Avoid the two errors — over-screening as if it were MLH1, or dismissing it as clinically silent.
GeneReviews: Lynch Syndrome (Idos & Valle, 2021); Prospective Lynch Syndrome Database (Møller et al.).
Note: Not an MMR gene itself: a 3'-end EPCAM deletion silences the adjacent MSH2 by promoter hypermethylation. Behaves colorectal-predominant with lower extracolonic risk than a true MSH2 variant; endometrial risk tracks with how much of MSH2 is silenced.
What to tell the patient: Explain it acts through MSH2 but with a colorectal-heavy pattern; the gyn-cancer counseling is lighter than MSH2 and depends on the specific deletion — genetics will clarify.
GeneReviews: Lynch Syndrome (Idos & Valle, 2021).
Surveillance & management
Colonoscopy — the one that saves lives
Every 1–2 years. Start at 20–25 for MLH1/MSH2 (or 2–5 years before the earliest colorectal cancer in the family, whichever is earlier); MSH6/PMS2 are later-onset, so guidelines commonly start ~30–35. Lifelong. This is the intervention with proven mortality benefit.
Gynecologic (endometrial / ovarian)
No screening test has shown mortality benefit — counsel on symptoms (any postmenopausal or abnormal bleeding → prompt evaluation); endometrial biopsy ± transvaginal ultrasound may be considered. Risk-reducing hysterectomy + BSO after childbearing is the definitive option (gyn-onc directed) — especially relevant for MSH2/MSH6.
Aspirin (chemoprevention)
The CAPP2 trial showed daily aspirin substantially reduces colorectal cancer in Lynch, with benefit sustained at 10 years. Can be considered — dose and candidacy individualized to bleeding risk and health status.
Gastric / urinary
Test and treat H. pylori. Consider upper endoscopy every 3–5 years from age 30–35, especially with a family history of gastric cancer or Asian ancestry. Consider annual urinalysis with cytology from 30–35 where family history warrants (urothelial risk, strongest with MSH2).
The family-physician move
- Suspect it — young colorectal/endometrial cancer, multiple Lynch cancers in the family, or an MSI-H tumor. Run PREMM5 if unsure.
- Make sure the tumor was MMR/MSI tested; refer to genetics for germline testing.
- Once confirmed, own the colonoscopy schedule — this is where primary care changes the outcome.
- Test/treat H. pylori; discuss aspirin; refer to gyn-onc for the hysterectomy/BSO conversation after childbearing.
See Inheritance & Family History for cascade testing of relatives once a family variant is known.
Gene-specific risks from the Prospective Lynch Syndrome Database (Møller et al.) via GeneReviews: Lynch Syndrome (Idos & Valle, 2021); surveillance per GeneReviews / NCCN; aspirin per Burn et al. (CAPP2, Lancet). Autosomal dominant — first-degree relatives have a 50% chance of carrying a known familial variant. General education for clinicians, not a substitute for formal genetic counseling.