Is CHEK2 p.Phe169fs (c.507del) pathogenic?

CHEK2 p.Phe169fs (c.507del) is classified Pathogenic in CHEK2 (ClinVar, Multiple submitters, 11 submitters; last evaluated 2025-12-22). Very rare (popmax 0.000339%, nfe); Associated with prostate cancer, hereditary.

What condition is associated with CHEK2 p.Phe169fs (c.507del)?

CHEK2 p.Phe169fs (c.507del) is associated with prostate cancer, hereditary, colorectal cancer, hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Phe169fs (c.507del) in the general population?

CHEK2 p.Phe169fs (c.507del) is very rare (popmax 0.000339%, nfe) (gnomAD).

How is Familial prostate cancer inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

CHEK2 p.Phe169fs

c.507del · rs587780183 · VCV128079

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Conditions

prostate cancer, hereditary

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 4 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.8	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 0.000339% European (non-Finnish) · 4/1,180,004 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000248% 4/1,614,084 alleles · very rare exomes 4/1,461,834 · genomes 0/152,250 · 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: CHEK2
Protein: p.Phe169fs
Coding: c.507del
MANE Select: NM_007194
dbSNP: rs587780183
Type: Deletion
Location: chr22:28725062 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 169: the fha domain; a β-strand

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

Disease context

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

Also linked: colorectal cancer hereditary neoplastic syndrome hereditary breast carcinoma CHEK2-related cancer predisposition

For Familial prostate cancer (Orphanet):

Inheritance: Not applicable
Onset: Adult
Prevalence: 1-9 / 100 000 (United States)

Similar variants

CHEK2 p.Phe169_Val170delinsLeu Uncertain significance ★★ same residue
CHEK2 p.Phe169Ile Uncertain significance ★★ ⚠ same residue
CHEK2 p.Phe169Leu Uncertain significance ★★ ⚠ same residue
CHEK2 p.Phe169Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Phe169Val Uncertain significance ★★ ⚠ same residue
CHEK2 p.Phe169= Benign/Likely benign ★★ same residue
CHEK2 p.Phe169Cys Uncertain significance ★ ⚠ same residue
CHEK2 c.1096-3_1098del 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-phe169fs (accessed [today's date]).

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