Is MSH2 p.Pro27Ser (c.79C>T) pathogenic?

MSH2 p.Pro27Ser (c.79C>T) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 6 submitters; last evaluated 2025-12-29). AlphaMissense: likely benign (0.1158); Very rare (popmax 0.00176%, amr); Associated with Lynch syndrome 1.

What condition is associated with MSH2 p.Pro27Ser (c.79C>T)?

MSH2 p.Pro27Ser (c.79C>T) is associated with Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Pro27Ser (c.79C>T) in the general population?

MSH2 p.Pro27Ser (c.79C>T) is very rare (popmax 0.00176%, amr) (gnomAD).

How is Lynch syndrome inherited?

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

What do computational predictors say about MSH2 p.Pro27Ser (c.79C>T)?

AlphaMissense predicts likely benign (score 0.1158) — an in-silico prediction, not a clinical call.

MSH2 p.Pro27Ser

c.79C>T · rs878853826 · VCV827377

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.1158 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00176%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Lynch syndrome 1

Computational evidence

Protein change
AlphaMissense	0.1158	likely benign
REVEL	0.601	indeterminate
SaProt	LLR -8.05	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1.8, phastCons 1
Regional constraint	o/e 1.30	unconstrained · MANE · 80 kb · p 4.9e-24 · regional, not allelic
Overall
CADD	21.7	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00176% Admixed American · 1/56,884 alleles

Overall 0.000125% 2/1,598,242 alleles · very rare exomes 2/1,445,884 · genomes 0/152,358 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00176%	56,884
Finnishnot grpmax-eligible	0.00162%	61,680

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.Pro27Ser
Coding: c.79C>T
MANE Select: NM_000251
dbSNP: rs878853826
Type: single nucleotide variant
Location: chr2:47403270 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB

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.Pro27= Benign/Likely benign ★★ same residue
MSH2 p.Pro27Ala Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro27Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro27Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro27Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 p.Pro27Thr Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH2 c.1076+1G>A Pathogenic ★★★ same condition
MSH2 c.1076+1G>T 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-pro27ser (accessed [today's date]).

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