Is MSH6 p.Pro898= (c.2694T>C) pathogenic?

MSH6 p.Pro898= (c.2694T>C) is classified Benign/Likely benign in MSH6 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-09-19). Very rare (popmax 0.00237%, nfe); Associated with Lynch syndrome 5.

What condition is associated with MSH6 p.Pro898= (c.2694T>C)?

MSH6 p.Pro898= (c.2694T>C) is associated with Lynch syndrome 5, Lynch syndrome, hereditary neoplastic syndrome (ClinVar).

How common is MSH6 p.Pro898= (c.2694T>C) in the general population?

MSH6 p.Pro898= (c.2694T>C) is very rare (popmax 0.00237%, nfe) (gnomAD).

How is Lynch syndrome inherited?

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

MSH6 p.Pro898=

c.2694T>C · rs769668106 · VCV525896

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00237%, nfe)

Conditions

Lynch syndrome 5

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 -1.3	GERP -1.7, phastCons 0.001
Overall
CADD	4.001	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00237% European (non-Finnish) · 28/1,180,030 alleles

Filtering AF 0.00164% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00142%

Overall 0.00173% 28/1,614,062 alleles · very rare exomes 27/1,461,852 · genomes 1/152,210 · 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: MSH6
Protein: p.Pro898=
Coding: c.2694T>C
MANE Select: NM_000179
dbSNP: rs769668106
Type: single nucleotide variant
Location: chr2:47800677 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 898: a β-strand

Full MSH6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome hereditary neoplastic syndrome

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MSH6 p.Pro898Leu Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro898Ser Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro898Thr Uncertain significance ★★ ⚠ same residue
MSH6 p.Pro898Ala Uncertain significance ★ ⚠ same residue
MSH6 p.Pro898Arg Conflicting classifications of pathogenicity ★ ⚠ same residue
MSH6 p.Pro898fs Pathogenic ★★ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A 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/msh6-p-pro898 (accessed [today's date]).

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