PMS1

Chr 2

PMS1 homolog 1, mismatch repair system component

Also known as: HNPCC3, MLH2, PMSL1, hPMS1

NCBI Gene: 5378ENSG00000064933UniProt: P54277OMIM: 600258

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]

GeneReviewsOMIMResearchGenerating clinical summary…
MultiplemechanismLOEUF 1.01
Clinical Summary— PMS1
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Gene-Disease Validity (ClinGen)
Lynch syndrome · ADRefuted

Refuted — evidence has disproved this relationship

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Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
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ClinVar Variants
5 unique Pathogenic / Likely Pathogenic· 101 VUS of 186 total submissions
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Clinical Trials
3 active or recruiting trials — potential therapeutic options may be available
Explore recent and relevant literature in Research Assistant →
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GeneReview available — PMS1
Authoritative clinical overview · Recommended first read
Open GeneReview ↗

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Tolerant — LoF & missense variants common in population
LoF Constraint?
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?
0.62Z-score
OE missense 0.92 (0.85–0.99)
441 obs / 479.5 exp
Tolerant

Mild missense constraint

Observed / Expected Ratios?
LoF OE?0.76 (0.57–1.01)
0≤0.351.4
Missense OE?0.92 (0.85–0.99)
0≤0.61.4
Synonymous OE?0.84
0≤1.21.6
LoF obs/exp: 32 / 42.4Missense obs/exp: 441 / 479.5Syn Z: 1.61

This gene — mechanism propensity

DN
0.6843th %ile
GOF
0.3094th %ile
LOF
0.4234th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and loss-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median
LOF60% of P/LP variants are LoF

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

ClinVar Variant Classifications

186 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic1
Likely Pathogenic4
VUS101
Likely Benign22
Benign29
Conflicting1
1
Pathogenic
4
Likely Pathogenic
101
VUS
22
Likely Benign
29
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
1
0
0
0
1
Likely Pathogenic
2
2
0
0
4
VUS
6
94
1
0
101
Likely Benign
1
15
1
5
22
Benign
1
9
16
3
29
Conflicting
—1
Total11120188158

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

View in ClinVar →

28 pathogenic / likely-pathogenic (of 30) ClinVar copy-number / structural variants overlap PMS1 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →

Protein Context — Lollipop Plot

PMS1 · protein map & ClinVar variants

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

External Resources

Links to major genomics databases and tools

Franklin by Genoox
AI-powered variant curation and clinical analysis
DECIPHER
Genomic variants and phenotypes in rare disease patients