PMS2

Chr 7AR

PMS1 homolog 2, mismatch repair system component

Also known as: HNPCC4, LYNCH4, MLH4, MMRCS4, PMS-2, PMS2CL, PMSL2

NCBI Gene: 5395 ENSG00000122512 UniProt: P54278

The protein encoded by this gene is a key component of the mismatch repair system that functions to correct DNA mismatches and small insertions and deletions that can occur during DNA replication and homologous recombination. This protein forms heterodimers with the gene product of the mutL homolog 1 (MLH1) gene to form the MutL-alpha heterodimer. The MutL-alpha heterodimer possesses an endonucleolytic activity that is activated following recognition of mismatches and insertion/deletion loops by the MutS-alpha and MutS-beta heterodimers, and is necessary for removal of the mismatched DNA. There is a DQHA(X)2E(X)4E motif found at the C-terminus of the protein encoded by this gene that forms part of the active site of the nuclease. Mutations in this gene have been associated with hereditary nonpolyposis colorectal cancer (HNPCC; also known as Lynch syndrome) and Turcot syndrome. [provided by RefSeq, Apr 2016]

Primary Disease Associations & Inheritance

Lynch syndrome 4MIM #614337

Mismatch repair cancer syndrome 4MIM #619101

592

ClinVar variants

Pathogenic / LP

0.00

pLI score

Active trials

Clinical Summary— PMS2

🧬

Gene-Disease Validity (ClinGen)

Lynch syndrome · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

3 total gene-disease associations curated

⚡

Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

📋

ClinVar Variants

72 Pathogenic / Likely Pathogenic· 224 VUS of 592 total submissions

💊

Clinical Trials

12 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.

1.27LOEUF

pLI 0.000

Z-score 0.15

OE 0.98 (0.76–1.27)

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.

-0.56Z-score

OE missense 1.07 (1.00–1.16)

502 obs / 468.1 exp

Tolerant

Tolerant to missense variation

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.0.98 (0.76–1.27)

0≤0.351.4

Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.07 (1.00–1.16)

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.1.10

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	33	0	22	0	55
Likely Pathogenic	12	0	5	0	17
VUS	4	190	29	1	224
Likely Benign	4	16	94	61	175
Benign	0	4	44	68	116
Conflicting	—				5
Total	53	210	194	130	592

PMS2

Primary Disease Associations & Inheritance

Population Genetics & Constraint

ClinVar Variant Classifications

Classification Summary

Curated Variants Distribution

Protein Context — Lollipop Plot

DECIPHER · Gene2Phenotype

Gene2Phenotype Curations

OMIM — Genotype-Phenotype Relationships

Gene Overview

ClinGen Curation

Disease Associations

External Resources

Variant Interpretation

Population Databases

Gene Resources