Is MSH2 p.Phe58= (c.174C>T) pathogenic?

MSH2 p.Phe58= (c.174C>T) is classified Benign/Likely benign in MSH2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2025-02-25). Absent from gnomAD v4.1; Associated with Lynch syndrome.

What condition is associated with MSH2 p.Phe58= (c.174C>T)?

MSH2 p.Phe58= (c.174C>T) is associated with Lynch syndrome, Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Phe58= (c.174C>T) in the general population?

MSH2 p.Phe58= (c.174C>T) is absent from gnomAD v4.1 (gnomAD).

How is Lynch syndrome inherited?

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

MSH2 p.Phe58=

c.174C>T · rs372189599 · VCV483754

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

gnomAD v4.1

Absent

absent from gnomAD v4.1

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 2.7	GERP 1.6, phastCons 1
Overall
CADD	17.92	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MSH2
Protein: p.Phe58=
Coding: c.174C>T
MANE Select: NM_000251
dbSNP: rs372189599
Type: single nucleotide variant
Location: chr2:47403365 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 58: 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.Phe58Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Phe58Ser Uncertain significance ★ ⚠ same residue
MSH2 p.Phe58Tyr Uncertain significance ★ ⚠ same residue
MSH2 p.Phe58Ter Pathogenic ★★ same residue
MSH2 p.Phe58fs Likely pathogenic ★ 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

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-phe58 (accessed [today's date]).

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