Is CHEK2 p.Phe292fs (c.876del) pathogenic?

CHEK2 p.Phe292fs (c.876del) is classified Pathogenic in CHEK2 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2024-08-27). Very rare (popmax 0.00271%, afr); Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Phe292fs (c.876del)?

CHEK2 p.Phe292fs (c.876del) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Phe292fs (c.876del) in the general population?

CHEK2 p.Phe292fs (c.876del) is very rare (popmax 0.00271%, afr) (gnomAD).

CHEK2 p.Phe292fs

c.876del · rs772683219 · VCV234765

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00271%, afr)

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 8 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6	GERP 1.4, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00271% African / African-American · 2/73,772 alleles

Filtering AF 0.00064% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000493%

Overall 0.00107% 15/1,403,714 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00271%	36,886
European (non-Finnish)	0.00115%	87,228

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.Phe292fs
Coding: c.876del
MANE Select: NM_007194
dbSNP: rs772683219
Type: Deletion
Location: chr22:28703537 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 292: a β-strand; the protein kinase domain

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.Phe292Ser Uncertain significance ★★ ⚠ same residue
CHEK2 p.Phe292= Likely benign ★★ same residue
CHEK2 p.Phe292Ile Uncertain significance ★ same residue
CHEK2 p.Phe292Leu Uncertain significance ★ ⚠ same residue
CHEK2 c.1096-3_1098del Likely pathogenic ★★ same condition
CHEK2 c.1375+1_1375+2del Likely pathogenic ★★ same condition
CHEK2 c.1375+1del Likely pathogenic ★★ same condition
CHEK2 c.1461+1del 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-phe292fs (accessed [today's date]).

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