Is CHEK2 p.Ser5fs (c.14_20del) pathogenic?

CHEK2 p.Ser5fs (c.1420del) is classified Pathogenic/Likely pathogenic in CHEK2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-05). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with CHEK2 p.Ser5fs (c.14_20del)?

CHEK2 p.Ser5fs (c.14_20del) is associated with hereditary breast ovarian cancer syndrome, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ser5fs (c.14_20del) in the general population?

CHEK2 p.Ser5fs (c.14_20del) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

CHEK2 p.Ser5fs

c.14_20del · rs757016287 · VCV233394

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

hereditary breast ovarian cancer 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 -0.45	GERP -3

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.47e-05% European (non-Finnish) · 1/1,180,032 alleles

Overall 6.84e-05% 1/1,461,628 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.Ser5fs
Coding: c.14_20del
MANE Select: NM_007194
dbSNP: rs757016287
Type: Deletion
Location: chr22:28734702 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 5: the 'disordered' region

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

Disease context

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

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

CHEK2 p.Ser5= Benign/Likely benign ★★ same residue
CHEK2 p.Ser5Ter Pathogenic ★ same residue
CHEK2 p.Ser5Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser5Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ser5Pro Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser5Trp Uncertain significance ★ ⚠ same residue
CHEK2 c.1096-3_1098del Likely pathogenic ★★ same condition
CHEK2 c.1375+1_1375+2del 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-ser5fs (accessed [today's date]).

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