Is MSH2 p.Pro69= (c.207G>A) pathogenic?

MSH2 p.Pro69= (c.207G>A) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-12-06). Very rare (popmax 0.000256%, nfe); Associated with Lynch syndrome 1.

What condition is associated with MSH2 p.Pro69= (c.207G>A)?

MSH2 p.Pro69= (c.207G>A) is associated with Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Pro69= (c.207G>A) in the general population?

MSH2 p.Pro69= (c.207G>A) is very rare (popmax 0.000256%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

MSH2 p.Pro69=

c.207G>A · rs1295445617 · VCV491793

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000256%, nfe)

Conditions

Lynch syndrome 1

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -5
Overall
CADD	10.95	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000256% European (non-Finnish) · 3/1,171,792 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000188% 3/1,597,086 alleles · very rare exomes 3/1,444,722 · genomes 0/152,364 · joint denominator

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.Pro69=
Coding: c.207G>A
MANE Select: NM_000251
dbSNP: rs1295445617
Type: single nucleotide variant
Location: chr2:47403398 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 69: a β-strand

Full MSH2 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: hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Pro69Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro69Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro69Ser Uncertain significance ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>C Likely pathogenic ★★★ same condition
MSH2 c.1077-1G>T Likely pathogenic ★★★ same condition
MSH2 c.1077-2A>C 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-pro69 (accessed [today's date]).

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