Lynch syndrome: genes and variants
Lynch syndrome is linked to 7 analyzed proteins (MLH1, MSH2, MSH6, PMS2, MLH3, EPCAM and PMS1). 109 DNA variants are known to cause it; 1,295 more are uncertain, and 6 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Also known as: Lynch syndrome 1; Lynch syndrome 2; Lynch syndrome 4; Lynch syndrome 5; Lynch syndrome 8
Genes linked to Lynch syndrome
MLH1: DNA mismatch repair protein Mlh1
The protein partners with PMS2 to form MutL alpha, a core complex in post-replicative DNA mismatch repair. By helping correct copying errors in DNA, MLH1 protects genome stability, and inherited MLH1 variants are a major cause of Lynch syndrome.
64 disease-causing and 223 uncertain variants in MLH1 are linked to Lynch syndrome.
MSH2: DNA mismatch repair protein Msh2
The protein forms mismatch-recognition complexes with MSH6 or MSH3 that detect base mismatches and insertion-deletion loops in DNA. This first step of mismatch repair helps preserve genome integrity, and inherited MSH2 variants are associated with Lynch syndrome.
22 disease-causing and 313 uncertain variants in MSH2 are linked to Lynch syndrome.
MSH6: DNA mismatch repair protein Msh6
Together with MSH2, it recognizes single-base mismatches and small insertion-deletion loops during DNA replication and initiates mismatch repair. Germline loss-of-function variants cause Lynch syndrome, while biallelic variants can cause constitutional mismatch-repair deficiency.
12 disease-causing and 256 uncertain variants in MSH6 are linked to Lynch syndrome.
PMS2: Mismatch repair endonuclease PMS2
Together with MLH1, it provides endonuclease activity needed to complete DNA mismatch repair after replication errors are recognized. Germline loss-of-function variants cause Lynch syndrome, while biallelic variants cause constitutional mismatch-repair deficiency.
11 disease-causing and 473 uncertain variants in PMS2 are linked to Lynch syndrome.
MLH3: DNA mismatch repair protein Mlh3
It partners with other mismatch-repair proteins and also participates in meiotic crossover formation. Biallelic or monoallelic variants have been investigated in cancer predisposition, but the clinical significance of many MLH3 variants remains less firmly established than for core Lynch-syndrome genes.
0 disease-causing and 0 uncertain variants in MLH3 are linked to Lynch syndrome.
EPCAM: Epithelial cell adhesion molecule
It supports epithelial organization and signaling at cell-cell interfaces. Deletions extending through its 3-prime end can silence neighboring MSH2 and cause Lynch syndrome, while biallelic loss-of-function variants cause congenital tufting enteropathy.
0 disease-causing and 24 uncertain variants in EPCAM are linked to Lynch syndrome.
PMS1: PMS1 protein homolog 1
It participates in DNA mismatch repair through complexes with MLH-family proteins, although its role is less central than that of PMS2 in canonical MutLalpha activity. Germline variants have been investigated in cancer predisposition, but many reported associations remain less definitive than core Lynch-syndrome genes.
0 disease-causing and 6 uncertain variants in PMS1 are linked to Lynch syndrome.
Weakly linked (only a few uncertain records): CDH1.
Where Lynch syndrome variants cluster
- MSH2 Interaction with EXO1 (positions 601–671): 3 of 22 disease-causing changes, 1.8× more than its size predicts.
Known disease-causing variants in Lynch syndrome
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| MLH1 T82I | 82 | Disease-causing (★★★) | |
| MLH1 T82A | 82 | Disease-causing (★★★) | |
| MLH1 E102K | 102 | Disease-causing (★★★) | |
| MLH1 E102D | 102 | Disease-causing (★★★) | |
| MLH1 M1T | 1 | Disease-causing (★★★) | |
| MLH1 M1K | 1 | Disease-causing (★★★) | |
| MLH1 M1R | 1 | Disease-causing (★★★) | |
| MLH1 A21E | 21 | Disease-causing (★★★) | |
| MLH1 A21V | 21 | Disease-causing (★★★) | |
| MLH1 C77Y | 77 | Disease-causing (★★★) | |
| MLH1 C77R | 77 | Disease-causing (★★★) | |
| MLH1 G101D | 101 | Disease-causing (★★★) | |
| MLH1 G101S | 101 | Disease-causing (★★★) | |
| MLH1 R182G | 182 | Disease-causing (★★★) | |
| MLH1 S295G | 295 | Disease-causing (★★★) | |
| MLH1 S295R | 295 | Disease-causing (★★★) | |
| MLH1 M1I | 1 | Disease-causing (★★★) | |
| MLH1 P28L | 28 | Disease-causing (★★★) | |
| MLH1 F80V | 80 | Disease-causing (★★★) | |
| MLH1 K84E | 84 | Disease-causing (★★★) | |
| MLH1 V185G | 185 | Disease-causing (★★★) | |
| MLH1 R226L | 226 | Disease-causing (★★★) | |
| MLH1 R226Q | 226 | Disease-causing (★★★) | |
| MLH1 K311E | 311 | Disease-causing (★★★) | |
| MLH1 I19F | 19 | Disease-causing (★★★) | |
| MLH1 A29G | 29 | Disease-causing (★★★) | |
| MLH1 A29S | 29 | Disease-causing (★★★) | |
| MLH1 R100P | 100 | Disease-causing (★★★) | |
| MLH1 R182K | 182 | Disease-causing (★★★) | |
| MLH1 R265S | 265 | Disease-causing (★★★) | |
| MLH1 R265P | 265 | Disease-causing (★★★) | |
| MLH1 S295N | 295 | Disease-causing (★★★) | |
| MLH1 N306K | 306 | Disease-causing (★★★) | |
| MLH1 H308P | 308 | Disease-causing (★★★) | |
| MSH2 V695M | 695 | Disease-causing (★★★) | |
| MLH1 I107R | 107 | Disease-causing (★★★) | |
| MLH1 T117R | 117 | Disease-causing (★★★) | |
| MLH1 S247P | 247 | Disease-causing (★★★) | |
| MSH6 A1055P | 1055 | Disease-causing (★★★) | |
| MLH1 I25F | 25 | Disease-causing (★★★) | |
| MLH1 N38K | 38 | Disease-causing (★★★) | |
| MLH1 D63V | 63 | Disease-causing (★★★) | |
| MLH1 A111V | 111 | Disease-causing (★★★) | |
| MLH1 A128P | 128 | Disease-causing (★★★) | |
| MLH1 G147E | 147 | Disease-causing (★★★) | |
| MLH1 V152G | 152 | Disease-causing (★★★) | |
| MLH1 L155R | 155 | Disease-causing (★★★) | |
| MLH1 G244D | 244 | Disease-causing (★★★) | |
| MLH1 L260R | 260 | Disease-causing (★★★) | |
| MLH1 I276R | 276 | Disease-causing (★★★) | |
| MLH1 D304V | 304 | Disease-causing (★★★) | |
| MLH1 L559P | 559 | Interaction with EXO1 | Disease-causing (★★★) |
| MLH1 H718P | 718 | Disease-causing (★★★) | |
| MLH1 L749P | 749 | Disease-causing (★★★) | |
| MLH1 R755G | 755 | Disease-causing (★★★) | |
| MSH2 P349R | 349 | Disease-causing (★★★) | |
| MLH1 R127K | 127 | Disease-causing (★★★) | |
| MLH1 K70E | 70 | Disease-causing (★★★) | |
| MLH1 A281V | 281 | Disease-causing (★★★) | |
| MLH1 Q701H | 701 | Disease-causing (★★★) |
Showing 60 of 109.
Uncertain variants in Lynch syndrome that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| MLH1 L260H | 260 | Conflicting reports (★) | +6: L260R at the same position is pathogenic; REVEL 0.951 | |
| MLH1 N306I | 306 | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; N306K at the same position is pathogenic; REVEL 0.967 | |
| MSH2 P696A | 696 | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; P696R at the same position is pathogenic; REVEL 0.904 | |
| MSH2 L310H | 310 | Uncertain (★★) | +6: L310R at the same position is pathogenic; REVEL 0.981 | |
| MSH2 V695A | 695 | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; V695M at the same position is pathogenic; REVEL 0.934 | |
| MLH1 A128T | 128 | Uncertain (★★) | +6: 2 other pathogenic changes within 3 positions; A128P at the same position is pathogenic; REVEL 0.855 |
Which prediction tools work for Lynch syndrome
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- AlphaGenome (regulatory): 96 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 93 out of 100
- EVE: 93 out of 100
- REVEL: 92 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- AlphaMissense: 88 out of 100
- SIFT: 88 out of 100
- MutPred2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 84 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- ESM1b (LLR): 83 out of 100
- MetaLR: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 80 out of 100
- AlphaGenome (splicing): 71 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Hereditary nonpolyposis colorectal neoplasms is also caused by MLH1 variants; they fall partly in the same places as the Lynch syndrome variants (51 disease-causing).
- Colorectal cancer, hereditary nonpolyposis, type 6 is also caused by MLH1 variants; they fall partly in the same places as the Lynch syndrome variants (17 disease-causing).
- Muir-Torré syndrome is also caused by MLH1 variants; they fall partly in the same places as the Lynch syndrome variants (4 disease-causing).
- Hereditary nonpolyposis colon cancer is also caused by MLH1 variants; they fall partly in the same places as the Lynch syndrome variants (4 disease-causing).
- Mismatch repair cancer syndrome is also caused by MLH1 variants; they fall partly in the same places as the Lynch syndrome variants (4 disease-causing).
- Hereditary nonpolyposis colorectal neoplasms is also caused by MSH2 variants; they fall partly in the same places as the Lynch syndrome variants (12 disease-causing).
- Hereditary nonpolyposis colorectal neoplasms is also caused by MSH6 variants; they fall partly in the same places as the Lynch syndrome variants (14 disease-causing).
- Hereditary nonpolyposis colorectal neoplasms is also caused by PMS2 variants; they fall partly in the same places as the Lynch syndrome variants (12 disease-causing).
Diseases related to Lynch syndrome
- Endometrial carcinoma, also linked to MLH1, MLH3, MSH2, MSH6 and 1 more
- Hereditary nonpolyposis colorectal neoplasms, also linked to MLH1, MSH2, MSH6 and PMS2
- Ovarian cancer, also linked to MLH1, MSH2, MSH6 and PMS1
- Colorectal cancer, also linked to MLH1, MLH3, MSH2 and MSH6
- Gastric cancer, also linked to EPCAM, MLH1, MSH6 and PMS2
- Hereditary nonpolyposis colon cancer, also linked to MLH1, MSH2, MSH6 and PMS2
- Mismatch repair cancer syndrome, also linked to MLH1, MSH2, MSH6 and PMS2
- Breast and/or ovarian cancer, also linked to MLH1, MSH2, MSH6 and PMS2
- Colorectal cancer, hereditary nonpolyposis, type 6, also linked to MLH1 and MLH3
- Muir-Torré syndrome, also linked to MLH1 and MSH2
- Lynch-like syndrome, also linked to MLH1 and MSH6
- Familial cancer of breast, also linked to EPCAM
Frequently asked questions
Which genes are linked to Lynch syndrome?
In CATVariant, Lynch syndrome is linked to 7 analyzed proteins: MLH1 (DNA mismatch repair protein Mlh1), MSH2 (DNA mismatch repair protein Msh2), MSH6 (DNA mismatch repair protein Msh6), PMS2 (Mismatch repair endonuclease PMS2), MLH3 (DNA mismatch repair protein Mlh3), EPCAM (Epithelial cell adhesion molecule) and 1 more.
How many genetic variants are linked to Lynch syndrome?
2,010 variants: 109 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 1,295 are of uncertain significance or have conflicting reports.
Which uncertain variants in Lynch syndrome look disease-causing?
6 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example MLH1 L260H, MLH1 N306I, MSH2 P696A, MSH2 L310H and MSH2 V695A. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Lynch syndrome?
Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.93, based on 23 disease-causing and 180 harmless variants).
About this data
Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.
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