PMS1

Chr 2

PMS1 homolog 1, mismatch repair system component

Also known as: HNPCC3, MLH2, PMSL1, hPMS1

NCBI Gene: 5378ENSG00000064933UniProt: P54277

This gene encodes a protein belonging to the DNA mismatch repair mutL/hexB family. This protein is thought to be involved in the repair of DNA mismatches, and it can form heterodimers with MLH1, a known DNA mismatch repair protein. Mutations in this gene cause hereditary nonpolyposis colorectal cancer type 3 (HNPCC3) either alone or in combination with mutations in other genes involved in the HNPCC phenotype, which is also known as Lynch syndrome. [provided by RefSeq, Jul 2008]

186
ClinVar variants
32
Pathogenic / LP
0.00
pLI score
3
Active trials
Clinical Summary— PMS1
🧬
Gene-Disease Validity (ClinGen)
Lynch syndrome · ADRefuted

Refuted — evidence has disproved this relationship

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
32 Pathogenic / Likely Pathogenic· 102 VUS of 186 total submissions
💊
Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
1.01LOEUF
pLI 0.000
Z-score 1.48
OE 0.76 (0.57–1.01)
Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
0.62Z-score
OE missense 0.92 (0.85–0.99)
441 obs / 479.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.76 (0.57–1.01)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.92 (0.85–0.99)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.84
0≤1.21.6
LoF obs/exp: 32 / 42.4Missense obs/exp: 441 / 479.5Syn Z: 1.61

ClinVar Variant Classifications

186 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic28
Likely Pathogenic4
VUS102
Likely Benign22
Benign29
Conflicting1
28
Pathogenic
4
Likely Pathogenic
102
VUS
22
Likely Benign
29
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
27
0
28
Likely Pathogenic
1
2
1
0
4
VUS
2
93
7
0
102
Likely Benign
1
15
1
5
22
Benign
1
9
16
3
29
Conflicting
—1
Total6119528186

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

PMS1 · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
📖
GeneReview available — PMS1
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Microsatellite instability in colorectal cancer.
De' Angelis GL et al.·Acta Biomed
2018Review
Genetic modifiers of Huntington disease differentially influence motor and cognitive domains.
Lee JM et al.·Am J Hum Genet
2022
Therapeutic validation of MMR-associated genetic modifiers in a human ex vivo model of Huntington disease.
Ferguson R et al.·Am J Hum Genet
2024Functional
Lynch syndrome genes.
Peltomäki P·Fam Cancer
2005Review
Pathogenic variants reveal candidate genes for prostate cancer germline testing for men of African ancestry.
Gheybi K et al.·Nat Commun
2025
Therapeutic targeting of mismatch repair proteins in triplet repeat expansion diseases.
Marzec P et al.·DNA Repair (Amst)
2025Review
Investigation of discordant sibling pairs from hereditary breast cancer families and analysis of a rare PMS1 variant.
Landry KK et al.·Cancer Genet
2022
Identification of a novel germline frameshift mutation p.D300fs of PMS1 in a patient with hepatocellular carcinoma: A case report and literature review.
Li X et al.·Medicine (Baltimore)
2020Review
Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.
Rifkin AS et al.·Clin Lung Cancer
2023
Interrupting sequence variants and age of onset in Huntington's disease: clinical implications and emerging therapies.
Wright GEB et al.·Lancet Neurol
2020Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Solid TumorAdvanced Solid TumorMetastatic Cancer

KPMNG Study of MOlecular Profiling Guided Therapy Based on Genomic Alterations in Advanced Solid Tumors II

RECRUITING
NCT05525858Seoul National University Bundang HospitalStarted 2022-09-28
AlectinibAtezolizumabErlotinib
Pancreas CancerPeutz-Jeghers Syndrome (PJS)Gene Mutation

The Cancer of the Pancreas Screening-5 CAPS5)Study

RECRUITING
NCT02000089Phase PHASE3Johns Hopkins UniversityStarted 2014-01-06
SecretinMRITumor marker gene test with CA19-9
Lymphoma, Non-HodgkinMultiple MyelomaAdvanced Solid Tumors

TAPUR: Testing the Use of Food and Drug Administration (FDA) Approved Drugs That Target a Specific Abnormality in a Tumor Gene in People With Advanced Stage Cancer

RECRUITING
NCT02693535Phase PHASE2American Society of Clinical OncologyStarted 2016-03-14
PalbociclibSunitinibTemsirolimus

External Resources

Links to major genomics databases and tools