Is MLH1 p.Phe80fs (c.239del) pathogenic?

MLH1 p.Phe80fs (c.239del) is classified Pathogenic/Likely pathogenic in MLH1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-10). No gnomAD frequency available for this variant; Associated with Lynch syndrome 2.

What condition is associated with MLH1 p.Phe80fs (c.239del)?

MLH1 p.Phe80fs (c.239del) is associated with Lynch syndrome 2 (ClinVar).

How common is MLH1 p.Phe80fs (c.239del) in the general population?

MLH1 p.Phe80fs (c.239del) is no gnomAD frequency available for this variant (gnomAD).

How is Lynch syndrome inherited?

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

MLH1 p.Phe80fs

c.239del · rs2470756105 · VCV2674545

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

Lynch syndrome 2

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	frameshift	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 3 of 19
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.42	phastCons 0.98

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

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: MLH1
Protein: p.Phe80fs
Coding: c.239del
MANE Select: NM_000249
dbSNP: rs2470756105
Type: Deletion
Location: chr3:37000985 (GRCh38)
Gene constraint: LOEUF 0.639 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.89 · 13 PDB
Residue 80: a UniProt-annotated variant site (in lynch2; decreased mismatch repair activity)

Full MLH1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Lynch syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

MLH1 p.Phe80= Conflicting classifications of pathogenicity ★ same residue
MLH1 p.Phe80_Thr81del Uncertain significance ★ same residue
MLH1 c.1896+1del Likely pathogenic ★★★ same condition
MLH1 c.208-1_208del Pathogenic ★★★ same condition
MLH1 c.574_588+2del Likely pathogenic ★★★ same condition
MLH1 c.588+1del Likely pathogenic ★★★ same condition
MLH1 c.-139-2804_-139-2801del Pathogenic ★★★ same condition
MLH1 p.Ala29fs 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/mlh1-p-phe80fs (accessed [today's date]).

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