Is CHEK2 p.Ser56fs (c.165del) pathogenic?

CHEK2 p.Ser56fs (c.165del) is classified Pathogenic in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-15). Associated with hereditary neoplastic syndrome.

What condition is associated with CHEK2 p.Ser56fs (c.165del)?

CHEK2 p.Ser56fs (c.165del) is associated with hereditary neoplastic syndrome (ClinVar).

CHEK2 p.Ser56fs

c.165del · VCV4634712

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

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 2 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 7.8	GERP 1.5, phastCons 1

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

Variant & gene context

Gene: CHEK2
Protein: p.Ser56fs
Coding: c.165del
MANE Select: NM_007194
Type: Deletion
Location: chr22:28734557 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 56: 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

Similar variants

CHEK2 p.Ser56Gly Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser56Ile 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.1543-11_1543-2del Likely pathogenic ★★ same condition
CHEK2 c.319+1del Likely pathogenic ★★ same condition
CHEK2 c.444+1del Pathogenic/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-ser56fs (accessed [today's date]).

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