Is PMS2 p.Met1Val (c.1A>G) pathogenic?

PMS2 p.Met1Val (c.1A>G) is classified Likely pathogenic in PMS2 (ClinVar, Expert panel, 24 submitters; last evaluated 2017-06-30). Very rare (popmax 0.0028%, nfe); Associated with Lynch syndrome 1.

What condition is associated with PMS2 p.Met1Val (c.1A>G)?

PMS2 p.Met1Val (c.1A>G) is associated with Lynch syndrome 1, Lynch syndrome, mismatch repair cancer syndrome 1 (ClinVar).

How common is PMS2 p.Met1Val (c.1A>G) in the general population?

PMS2 p.Met1Val (c.1A>G) is very rare (popmax 0.0028%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PMS2 p.Met1Val

c.1A>G · rs587779333 · VCV91323

Likely pathogenic Expert panel

Classification

Likely pathogenic

ClinVar

Review

Expert panel ★★★☆

ClinVar · 24 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0028%, nfe)

Conditions

Lynch syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
REVEL	0.546	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.7	phastCons 1
Overall
CADD	21.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0028% European (non-Finnish) · 33/1,179,848 alleles

Filtering AF 0.002% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00176%

Overall 0.00242% 39/1,612,468 alleles · very rare exomes 34/1,460,242 · genomes 5/152,226 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0028%	35,753
African / African-American	0.00267%	37,454
South Asian	0.0022%	45,513
Admixed American	0.00167%	60,008
Remaining individualsnot grpmax-eligible	0.0016%	62,354

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: PMS2
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_000535
dbSNP: rs587779333
Type: single nucleotide variant
Location: chr7:6009019 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 1 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome mismatch repair cancer syndrome 1 Lynch syndrome 4 hereditary neoplastic syndrome hereditary nonpolyposis colon cancer mismatch repair cancer syndrome 4

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Met1Arg Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Met1Ile Pathogenic ★★ same residue
PMS2 p.Met1Leu Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Met1Lys Pathogenic/Likely pathogenic ★★ same residue
PMS2 p.Met1Thr Pathogenic ★★ same residue
PMS2 c.1144+2T>A Likely pathogenic ★★★ same condition
PMS2 c.163+2T>C Likely pathogenic ★★★ same condition
PMS2 c.164-2A>G Likely pathogenic ★★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pms2-p-met1val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown