Is CHEK2 p.Met1Phe (c.1_3delinsTTT) pathogenic?

CHEK2 p.Met1Phe (c.13delinsTTT) is classified Conflicting classifications of pathogenicity in CHEK2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2023-06-22). Absent from gnomAD; Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Met1Phe (c.1_3delinsTTT)?

CHEK2 p.Met1Phe (c.1_3delinsTTT) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Met1Phe (c.1_3delinsTTT) in the general population?

CHEK2 p.Met1Phe (c.1_3delinsTTT) is absent from gnomAD (gnomAD).

CHEK2 p.Met1Phe

c.1_3delinsTTT · rs2518136497 · VCV1794563

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

Consequence

start-loss

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	start-loss	predicted loss-of-function in a haploinsufficient gene (ClinGen)
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.4	GERP 1.5, phastCons 1

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: CHEK2
Protein: p.Met1Phe
Coding: c.1_3delinsTTT
MANE Select: NM_007194
dbSNP: rs2518136497
Type: Indel
Location: chr22:28734719 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 1: the 'disordered' region

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

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

Also linked: hereditary breast carcinoma

Similar variants

CHEK2 p.Met1fs Likely pathogenic ★ same residue
CHEK2 p.Met1Thr Uncertain significance ★★ same residue
CHEK2 p.Met1Ile Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Met1Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Met1Lys Uncertain significance ★ same residue
CHEK2 p.Met1Val Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 c.1009-118_1009-87delinsC Likely pathogenic ★★ same condition
CHEK2 c.847-14_847-2delinsGG 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/chek2-p-met1phe (accessed [today's date]).

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