Is CHEK2 p.Cys124fs (c.368_369dup) pathogenic?

CHEK2 p.Cys124fs (c.368369dup) is classified Pathogenic in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-05-19). Very rare (popmax 8.48e-05%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Cys124fs (c.368_369dup)?

CHEK2 p.Cys124fs (c.368_369dup) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Cys124fs (c.368_369dup) in the general population?

CHEK2 p.Cys124fs (c.368_369dup) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

CHEK2 p.Cys124fs

c.368_369dup · rs2518060139 · VCV1733879

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Conditions

hereditary neoplastic syndrome

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 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 8.8	GERP 1.7, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,930 alleles

Overall 6.84e-05% 1/1,461,736 alleles · very rare

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: CHEK2
Protein: p.Cys124fs
Coding: c.368_369dup
MANE Select: NM_007194
dbSNP: rs2518060139
Type: Microsatellite
Location: chr22:28725317 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 124: the fha domain; a β-strand

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.Cys124Phe Uncertain significance ★★ same residue
CHEK2 p.Cys124Tyr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Cys124= Benign/Likely benign ★★ same residue
CHEK2 p.Cys124Ter Likely pathogenic ★ same residue
CHEK2 p.Cys124Arg Uncertain significance ★ same residue
CHEK2 p.Cys124Ser Uncertain significance ★ ⚠ same residue
CHEK2 p.Cys124Trp Uncertain significance ★ ⚠ same residue
CHEK2 p.Glu263fs 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-cys124fs (accessed [today's date]).

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