All 5 criteria must be met to classify as Amsterdam II positive. Criteria met = offer germline MMR gene panel testing. Low sensitivity (~60%) — universal MMR-IHC of CRC tumours is supplementary.
≥ 3 relatives with Lynch-associated cancer
CRC, endometrial, small bowel, ureter, or renal pelvis — one must be a 1st-degree relative of the other two
≥ 2 successive generations affected
≥ 1 patient diagnosed before age 50
FAP (Familial Adenomatous Polyposis) excluded in CRC cases
No evidence of FAP phenotype in colorectal cancer cases
Tumours verified by pathology
Not self-report; histopathology confirmation required
Guidelines & Evidence
Clinical Details
Section 1
When to Use
When to Use
Identifying families that fulfil clinical criteria for Lynch syndrome (previously Hereditary Non-Polyposis Colorectal Cancer — HNPCC).
Determining which families should be offered germline MMR gene testing (MLH1, MSH2, MSH6, PMS2, EPCAM).
Endorsed by ASCO, ACMG, ESMO, and NCCN for hereditary CRC risk assessment.
Key Distinction
Amsterdam I covered CRC only. Amsterdam II expanded to all Lynch-associated cancers: CRC, endometrial, small bowel, ureter, and renal pelvis carcinomas.
Section 2
Formula & Logic
3-2-1 Rule — All Five Criteria Required
≥ 3 relatives with Lynch-associated cancer (CRC, endometrial, small bowel, ureter/renal pelvis ca) — one must be a 1st degree relative of the other two
≥ 2 successive generations affected
≥ 1 patient diagnosed before age 50
Familial adenomatous polyposis (FAP) excluded in affected CRC cases
Tumours verified by pathology (not self-report)
Lynch-Associated Cancer Spectrum
Cancer
Lifetime Risk (Lynch vs General)
Colorectal cancer
30–74% vs 4%
Endometrial cancer
28–60% vs 3%
Gastric cancer
6–13% vs < 1%
Ovarian cancer
9–12% vs 1–2%
Urinary tract (ureter/renal pelvis)
1–13% vs < 1%
Small bowel cancer
1–4% vs < 0.1%
Brain tumours
1–3% vs < 1%
Section 3
Pearls/Pitfalls
Key Pearls
Amsterdam criteria detect only ~60% of Lynch syndrome families — low sensitivity by design. Use alongside Bethesda guidelines and universal tumour MMR testing.
Up to 40% of Lynch families fail Amsterdam II — hence NCCN/ESMO now recommend reflex universal MMR IHC testing of ALL CRC tumours regardless of family history.
An MMR-deficient (dMMR) tumour on IHC/MSI testing in itself warrants germline referral regardless of Amsterdam status.
PREMM5 or MMRPredict computational models offer better sensitivity than Amsterdam criteria alone.
Section 4
Next Steps
Clinical Actions
01
Criteria met: Offer germline MMR gene panel (MLH1, MSH2, MSH6, PMS2, EPCAM) — refer to clinical genetics or certified counsellor.
Criteria not met but family history suspicious: Still perform tumour MMR-IHC/MSI; apply Bethesda Guidelines; offer PREMM5 score.
04
Negative germline testing in Amsterdam-positive family: Consider large rearrangement testing (MLPA) and Lynch-like syndrome workup (somatic MMR biallelic mutations).
Section 5
Evidence Appraisal
Primary Reference
New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC
Vasen HF et al. • Gastroenterology. 1999;116(6): 1453–1456
Section 6
Literature
Amsterdam I (1990)
The original Amsterdam Criteria (1990) were proposed by the International Collaborative Group on HNPCC, led by Hans Vasen, to bring consistency to clinical identification of HNPCC families before the MMR gene era. They required 3 relatives with CRC across 2 generations with 1 case under 50.
Amsterdam II (1999)
Revised in 1999 after identification of MMR genes revealed that Lynch syndrome caused a broader cancer spectrum beyond CRC. Amsterdam II expanded to include endometrial, small bowel, and urinary tract cancers. The criteria are now primarily historical benchmarks — universal MMR/MSI tumour testing has replaced these clinical criteria as the frontline Lynch syndrome detection strategy in most guideline-adherent healthcare systems.
