Is MSH2 p.Met1Val (c.1A>G) pathogenic?

MSH2 p.Met1Val (c.1A>G) is classified Uncertain significance in MSH2 (ClinVar, Expert panel, 10 submitters; last evaluated 2019-06-21). Ultra-rare (popmax 0.017%, mid); Associated with Lynch syndrome.

What condition is associated with MSH2 p.Met1Val (c.1A>G)?

MSH2 p.Met1Val (c.1A>G) is associated with Lynch syndrome, gastric cancer, Lynch syndrome 1 (ClinVar).

How common is MSH2 p.Met1Val (c.1A>G) in the general population?

MSH2 p.Met1Val (c.1A>G) is ultra-rare (popmax 0.017%, mid) (gnomAD).

How is Lynch syndrome inherited?

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

MSH2 p.Met1Val

c.1A>G · rs267607911 · VCV90833

Uncertain significance Expert panel

Classification

Uncertain significance

ClinVar

Review

Expert panel ★★★☆

ClinVar · 10 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Rare

ultra-rare (popmax 0.017%, mid)

Conditions

Lynch syndrome

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	0.795	moderately pathogenic-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.3	GERP 2.5, phastCons 1
Overall
CADD	22.6	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 0.017% Middle Eastern · 1/5,888 alleles

Filtering AF 0.000905% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000451%

Overall 0.000753% 12/1,594,238 alleles · ultra-rare exomes 12/1,441,876 · genomes 0/152,362 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.017%	5,888
South Asian	0.00341%	29,351
Admixed American	0.00176%	56,692
Finnishnot grpmax-eligible	0.00164%	60,982
European (non-Finnish)	0.000512%	195,292

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: MSH2
Protein: p.Met1Val
Coding: c.1A>G
MANE Select: NM_000251
dbSNP: rs267607911
Type: single nucleotide variant
Location: chr2:47403192 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB

Full MSH2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: gastric cancer Lynch syndrome 1 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Met1Leu Uncertain significance ★★★ same residue
MSH2 p.Met1Arg Uncertain significance ★★ same residue
MSH2 p.Met1Thr Uncertain significance ★★ same residue
MSH2 p.Met1Ile Uncertain significance ★ same residue
MSH2 p.Met1Lys Uncertain significance ★ same residue
MSH2 p.Met1fs Pathogenic ★ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T 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/msh2-p-met1val (accessed [today's date]).

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