Is MSH2 p.Ser558fs (c.1672dup) pathogenic?

MSH2 p.Ser558fs (c.1672dup) is classified Pathogenic in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-05-27). Associated with Muir-Torre syndrome.

What condition is associated with MSH2 p.Ser558fs (c.1672dup)?

MSH2 p.Ser558fs (c.1672dup) is associated with Muir-Torre syndrome, Lynch syndrome 1, mismatch repair cancer syndrome 2 (ClinVar).

MSH2 p.Ser558fs

c.1672dup · VCV3779898

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

Conditions

Muir-Torre syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 11 of 16
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.7	GERP 1.2, phastCons 1

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

Variant & gene context

Gene: MSH2
Protein: p.Ser558fs
Coding: c.1672dup
MANE Select: NM_000251
Type: Duplication
Location: chr2:47470973 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 558: an α-helix

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

Disease context

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

Also linked: Lynch syndrome 1 mismatch repair cancer syndrome 2

Similar variants

MSH2 p.Ser558_Leu559insTer Pathogenic ★★★ same residue
MSH2 p.Ser558del Conflicting classifications of pathogenicity ★ same residue
MSH2 p.Gln402fs Pathogenic ★★★ same condition
MSH2 p.Glu12fs Pathogenic ★★★ same condition
MSH2 p.Gly195delinsGluGluThrArgThrValTer Pathogenic ★★★ same condition
MSH2 p.Met779fs Pathogenic ★★★ same condition
MSH2 p.Tyr563fs Pathogenic ★★★ same condition
MSH2 p.Tyr98fs 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-ser558fs (accessed [today's date]).

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