Is MSH2 p.Pro618= (c.1854A>G) pathogenic?

MSH2 p.Pro618= (c.1854A>G) is classified Conflicting classifications of pathogenicity in MSH2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00446%, eas); Associated with Lynch syndrome.

What condition is associated with MSH2 p.Pro618= (c.1854A>G)?

MSH2 p.Pro618= (c.1854A>G) is associated with Lynch syndrome, Lynch syndrome 1, hereditary neoplastic syndrome (ClinVar).

How common is MSH2 p.Pro618= (c.1854A>G) in the general population?

MSH2 p.Pro618= (c.1854A>G) is very rare (popmax 0.00446%, eas) (gnomAD).

How is Lynch syndrome inherited?

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

MSH2 p.Pro618=

c.1854A>G · rs786203744 · VCV187451

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00446%, eas)

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 -5.1	GERP -3.6
Overall
CADD	0.395	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00446% East Asian · 2/44,886 alleles

Filtering AF 0.00106% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00124% 20/1,614,074 alleles · very rare exomes 18/1,461,872 · genomes 2/152,202 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00446%	22,443
African / African-American	0.004%	24,977
European (non-Finnish)	0.00127%	78,671

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.Pro618=
Coding: c.1854A>G
MANE Select: NM_000251
dbSNP: rs786203744
Type: single nucleotide variant
Location: chr2:47475119 (GRCh38)
Gene constraint: LOEUF 0.672 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 85.60 · 30 PDB
Residue 618: the 'interaction with exo1' region

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.Pro618Ala Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro618Leu Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro618Ser Uncertain significance ★★ ⚠ same residue
MSH2 p.Pro618fs Pathogenic/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
MSH2 c.1077-1G>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-pro618 (accessed [today's date]).

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