Is MSH3 p.Pro69fs (c.205_224del) pathogenic?

MSH3 p.Pro69fs (c.205224del) is classified Pathogenic in MSH3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-31). Very rare (popmax 0.000166%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with MSH3 p.Pro69fs (c.205_224del)?

MSH3 p.Pro69fs (c.205_224del) is associated with hereditary neoplastic syndrome (ClinVar).

How common is MSH3 p.Pro69fs (c.205_224del) in the general population?

MSH3 p.Pro69fs (c.205_224del) is very rare (popmax 0.000166%, nfe) (gnomAD).

MSH3 p.Pro69fs

c.205_224del · rs1285597974 · VCV2451067

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000166%, nfe)

Conditions

hereditary neoplastic syndrome

⚠ Built without this gene's context — gene constraint and dosage, protein structure, pathways, panels and related-variant links were not looked up for this page. why

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function; NMD-escape possible for C-terminal truncations
Splicing
SpliceAI	—	not looked up on this page · why
Constraint at this position
Conservation	phyloP 0.72	GERP -3.1, phastCons 0.97

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000166% European (non-Finnish) · 1/603,182 alleles

Overall 0.000122% 1/818,622 alleles · very rare exomes 1/734,740 · genomes 0/83,882 · 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: MSH3
Protein: p.Pro69fs
Coding: c.205_224del
MANE Select: NM_002439
dbSNP: rs1285597974
Type: Deletion
Location: chr5:80654924 (GRCh38)

Full MSH3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

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/msh3-p-pro69fs (accessed [today's date]).

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