Is MSH6 p.Phe119= (c.357C>T) pathogenic?

MSH6 p.Phe119= (c.357C>T) is classified Conflicting classifications of pathogenicity in MSH6 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2024-12-18). Very rare (popmax 8.47e-05%, nfe); Associated with mismatch repair cancer syndrome 3.

What condition is associated with MSH6 p.Phe119= (c.357C>T)?

MSH6 p.Phe119= (c.357C>T) is associated with mismatch repair cancer syndrome 3, endometrial carcinoma, Lynch syndrome 5 (ClinVar).

How common is MSH6 p.Phe119= (c.357C>T) in the general population?

MSH6 p.Phe119= (c.357C>T) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

MSH6 p.Phe119=

Q: How is Constitutional mismatch repair deficiency syndrome inherited?

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

c.357C>T · rs1298565919 · VCV823952

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

mismatch repair cancer syndrome 3

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.3	GERP 0.45, phastCons 1
Overall
CADD	13.17	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.19e-05% 1/1,614,214 alleles · very rare exomes 1/1,461,880 · genomes 0/152,334 · 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.Phe119=
Coding: c.357C>T
MANE Select: NM_000179
dbSNP: rs1298565919
Type: single nucleotide variant
Location: chr2:47791023 (GRCh38)
Gene constraint: LOEUF 0.841 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.93 · 8 PDB
Residue 119: the pwwp domain; a β-strand

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

Disease context

mismatch repair cancer syndrome 3 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma Lynch syndrome 5 hereditary neoplastic syndrome

For Constitutional mismatch repair deficiency syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

MSH6 p.Phe119Cys Uncertain significance ★★ ⚠ same residue
MSH6 p.Phe119Leu Uncertain significance ★★ ⚠ same residue
MSH6 p.Phe119Val Uncertain significance ★★ ⚠ same residue
MSH6 p.Phe119Tyr Uncertain significance ★ ⚠ same residue
MSH6 c.3172+1G>T Likely pathogenic ★★★ same condition
MSH6 c.3438+1G>A Likely pathogenic ★★★ same condition
MSH6 c.3439-1G>T Likely pathogenic ★★★ same condition
MSH6 c.3439-2A>G 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-phe119 (accessed [today's date]).

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