Is MSH2 p.Phe22= (c.66C>T) pathogenic?

MSH2 p.Phe22= (c.66C>T) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-11-24). Very rare (popmax 8.51e-05%, nfe); Associated with Lynch syndrome.

What condition is associated with MSH2 p.Phe22= (c.66C>T)?

MSH2 p.Phe22= (c.66C>T) is associated with Lynch syndrome, Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Phe22= (c.66C>T) in the general population?

MSH2 p.Phe22= (c.66C>T) is very rare (popmax 8.51e-05%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

MSH2 p.Phe22=

c.66C>T · rs200632093 · VCV1143593

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 8.51e-05%, nfe)

Conditions

Lynch syndrome

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 0.41	GERP 1.8, phastCons 0.99
Overall
CADD	13.47	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.51e-05% European (non-Finnish) · 1/1,175,196 alleles

Overall 6.25e-05% 1/1,600,488 alleles · very rare exomes 1/1,448,084 · genomes 0/152,404 · 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.Phe22=
Coding: c.66C>T
MANE Select: NM_000251
dbSNP: rs200632093
Type: single nucleotide variant
Location: chr2:47403257 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 22: an α-helix

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: Lynch syndrome 1 hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH2 p.Phe22Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Phe22Ile Conflicting classifications of pathogenicity ★ ⚠ 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
MSH2 c.1077-2A>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/msh2-p-phe22 (accessed [today's date]).

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