Hereditary nonpolyposis colorectal neoplasms: genes and variants
Hereditary nonpolyposis colorectal neoplasms is linked to 4 analyzed proteins (MLH1, MSH6, PMS2 and MSH2). 89 DNA variants are known to cause it; 6,248 more are uncertain, and 7 of those already look disease-causing on computable evidence.
Last updated 2026-09-30. Research information, not medical advice.
Genes linked to Hereditary nonpolyposis colorectal neoplasms
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.
51 disease-causing and 1,344 uncertain variants in MLH1 are linked to Hereditary nonpolyposis colorectal neoplasms.
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.
14 disease-causing and 1,697 uncertain variants in MSH6 are linked to Hereditary nonpolyposis colorectal neoplasms.
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.
12 disease-causing and 1,911 uncertain variants in PMS2 are linked to Hereditary nonpolyposis colorectal neoplasms.
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.
12 disease-causing and 1,293 uncertain variants in MSH2 are linked to Hereditary nonpolyposis colorectal neoplasms.
Weakly linked (only a few uncertain records): EPCAM and PMS1.
Known disease-causing variants in Hereditary nonpolyposis colorectal neoplasms
| Variant | Position | Protein part | Clinical label |
|---|---|---|---|
| MLH1 Y97H | 97 | Disease-causing (★★) | |
| MLH1 R127T | 127 | Disease-causing (★★) | |
| MLH1 Y130C | 130 | Disease-causing (★★) | |
| MLH1 D41V | 41 | Disease-causing (★★) | |
| MLH1 D41Y | 41 | Disease-causing (★★) | |
| MLH1 D63H | 63 | Disease-causing (★★) | |
| MLH1 D63V | 63 | Disease-causing (★★) | |
| MLH1 Y97C | 97 | Disease-causing (★★) | |
| MLH1 R127I | 127 | Disease-causing (★★) | |
| MLH1 Y130H | 130 | Disease-causing (★★) | |
| MLH1 S44F | 44 | Disease-causing (★★) | |
| MLH1 G67R | 67 | Disease-causing (★★) | |
| MSH6 W413R | 413 | Disease-causing (★★) | |
| PMS2 M1K | 1 | Disease-causing (★★) | |
| PMS2 M1R | 1 | Disease-causing (★★) | |
| PMS2 M1L | 1 | Disease-causing (★★) | |
| PMS2 M1I | 1 | Disease-causing (★★) | |
| MLH1 N38Y | 38 | Disease-causing (★★) | |
| MLH1 G98F | 98 | Disease-causing (★★) | |
| MLH1 A125E | 125 | Disease-causing (★★) | |
| MLH1 L555P | 555 | Interaction with EXO1 | Disease-causing (★★) |
| MLH1 L555R | 555 | Interaction with EXO1 | Disease-causing (★★) |
| MLH1 A681P | 681 | Disease-causing (★★) | |
| MLH1 Y684D | 684 | Disease-causing (★★) | |
| PMS2 S118T | 118 | Disease-causing (★★) | |
| MSH6 M1V | 1 | Disease-causing (★★) | |
| PMS2 S118N | 118 | Disease-causing (★★) | |
| PMS2 G271D | 271 | Disease-causing (★★) | |
| MLH1 M35K | 35 | Disease-causing (★★) | |
| MLH1 V51D | 51 | Disease-causing (★★) | |
| MLH1 L73P | 73 | Disease-causing (★★) | |
| MLH1 G101R | 101 | Disease-causing (★★) | |
| MLH1 I107K | 107 | Disease-causing (★★) | |
| MLH1 V194G | 194 | Disease-causing (★★) | |
| MLH1 L292P | 292 | Disease-causing (★★) | |
| MLH1 Y343D | 343 | Disease-causing (★★) | |
| MLH1 A539D | 539 | Interaction with EXO1 | Disease-causing (★★) |
| MLH1 L549R | 549 | Interaction with EXO1 | Disease-causing (★★) |
| MLH1 P640T | 640 | Interaction with EXO1 | Disease-causing (★★) |
| MLH1 P648R | 648 | Interaction with EXO1 | Disease-causing (★★) |
| MLH1 L653P | 653 | Disease-causing (★★) | |
| MLH1 E663D | 663 | Disease-causing (★★) | |
| MSH2 L270P | 270 | Disease-causing (★★) | |
| MSH2 C333F | 333 | Disease-causing (★★) | |
| MSH2 G338V | 338 | Disease-causing (★★) | |
| MSH2 R359I | 359 | Disease-causing (★★) | |
| MSH2 L440R | 440 | Disease-causing (★★) | |
| MSH2 L595P | 595 | Disease-causing (★★) | |
| MSH2 G674S | 674 | Disease-causing (★★) | |
| MSH2 Q690K | 690 | Disease-causing (★★) | |
| MSH2 F694I | 694 | Disease-causing (★★) | |
| MSH2 R711P | 711 | Disease-causing (★★) | |
| MSH6 P781S | 781 | Disease-causing (★★) | |
| MLH1 P399T | 399 | Disease-causing (★★) | |
| MLH1 A441D | 441 | Interaction with EXO1 | Disease-causing (★★) |
| MSH6 A1162D | 1162 | Disease-causing (★★) | |
| MSH6 R1334L | 1334 | Disease-causing (★★) | |
| PMS2 G279R | 279 | Disease-causing (★★) | |
| PMS2 G382R | 382 | Disease-causing (★★) | |
| PMS2 P844H | 844 | Disease-causing (★★) |
Showing 60 of 89.
Uncertain variants in Hereditary nonpolyposis colorectal neoplasms that look disease-causing
| Variant | Position | Protein part | Clinical label | Evidence |
|---|---|---|---|---|
| MLH1 D63Y | 63 | Conflicting reports (★) | +6: 4 other pathogenic changes within 3 positions; D63H at the same position is pathogenic; REVEL 0.989 | |
| MLH1 Y684S | 684 | Conflicting reports (★) | +6: 3 other pathogenic changes within 3 positions; Y684D at the same position is pathogenic; REVEL 0.920 | |
| MSH2 F694V | 694 | Uncertain (★) | +6: F694I at the same position is pathogenic; REVEL 0.938 | |
| MSH6 A1154V | 1154 | Uncertain (★★) | +6: A1154D at the same position is pathogenic; REVEL 0.944 | |
| MLH1 N306I | 306 | Uncertain (★★) | +6: N306D at the same position is pathogenic; REVEL 0.967 | |
| MLH1 Y684H | 684 | Uncertain (★★) | +6: 3 other pathogenic changes within 3 positions; Y684D at the same position is pathogenic; REVEL 0.946 | |
| MLH1 R127G | 127 | Uncertain (★★) | +6: 5 other pathogenic changes within 3 positions; R127T at the same position is pathogenic; REVEL 0.865 |
Which prediction tools work for Hereditary nonpolyposis colorectal neoplasms
How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).
- EVE: 91 out of 100
- AlphaMissense: 90 out of 100
- CATVariant: 88 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- PolyPhen-2: 87 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MutPred2: 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- SIFT: 86 out of 100
- ESM1b (LLR): 84 out of 100
- AlphaGenome (regulatory): 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- CADD: 82 out of 100
- REVEL: 82 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- MetaLR: 81 out of 100 (learned from overlapping clinical labels, so this is optimistic)
- phyloP: 71 out of 100
- AlphaGenome (splicing): 66 out of 100 (learned from overlapping clinical labels, so this is optimistic)
Same protein, different disease
- Lynch syndrome is also caused by MLH1 variants; they fall partly in the same places as the Hereditary nonpolyposis colorectal neoplasms variants (64 disease-causing).
- Colorectal cancer, hereditary nonpolyposis, type 6 is also caused by MLH1 variants; they fall partly in the same places as the Hereditary nonpolyposis colorectal neoplasms variants (17 disease-causing).
- Lynch syndrome is also caused by MSH6 variants; they fall mostly in different places as the Hereditary nonpolyposis colorectal neoplasms variants (12 disease-causing).
- Lynch syndrome is also caused by PMS2 variants; they fall partly in the same places as the Hereditary nonpolyposis colorectal neoplasms variants (11 disease-causing).
- Lynch syndrome is also caused by MSH2 variants; they fall partly in the same places as the Hereditary nonpolyposis colorectal neoplasms variants (22 disease-causing).
Diseases related to Hereditary nonpolyposis colorectal neoplasms
- Lynch syndrome, also linked to MLH1, MSH2, 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
- Endometrial carcinoma, also linked to MLH1, MSH2, MSH6 and PMS2
- Ovarian cancer, also linked to MLH1, MSH2 and MSH6
- Colorectal cancer, also linked to MLH1, MSH2 and MSH6
- Gastric cancer, also linked to MLH1, MSH6 and PMS2
- Muir-Torré syndrome, also linked to MLH1 and MSH2
- Lynch-like syndrome, also linked to MLH1 and MSH6
- Colorectal cancer, hereditary nonpolyposis, type 6, also linked to MLH1
- Breast-ovarian cancer, familial, susceptibility to, 1, also linked to MSH2
Frequently asked questions
Which genes are linked to Hereditary nonpolyposis colorectal neoplasms?
In CATVariant, Hereditary nonpolyposis colorectal neoplasms is linked to 4 analyzed proteins: MLH1 (DNA mismatch repair protein Mlh1), MSH6 (DNA mismatch repair protein Msh6), PMS2 (Mismatch repair endonuclease PMS2) and MSH2 (DNA mismatch repair protein Msh2).
How many genetic variants are linked to Hereditary nonpolyposis colorectal neoplasms?
6,411 variants: 89 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 6,248 are of uncertain significance or have conflicting reports.
Which uncertain variants in Hereditary nonpolyposis colorectal neoplasms look disease-causing?
7 uncertain variants reach the likely-pathogenic range of the ACMG/AMP points scale on computable evidence, for example MLH1 D63Y, MLH1 Y684S, MSH2 F694V, MSH6 A1154V and MLH1 N306I. These are leads for expert review, not diagnoses.
Which variant effect predictor works best for Hereditary nonpolyposis colorectal neoplasms?
Among tools not trained on clinical labels, EVE separates this disease's known disease-causing variants from harmless ones best (AUROC 0.91, based on 17 disease-causing and 114 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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