Is CHEK2 p.Pro522fs (c.1563dup) pathogenic?

CHEK2 p.Pro522fs (c.1563dup) is classified Uncertain significance in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-14). Ultra-rare (gnomAD MAF 2.891e-06); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Pro522fs (c.1563dup)?

CHEK2 p.Pro522fs (c.1563dup) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Pro522fs (c.1563dup) in the general population?

CHEK2 p.Pro522fs (c.1563dup) is ultra-rare (gnomAD MAF 2.891e-06) (gnomAD).

How is Hereditary breast cancer inherited?

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

CHEK2 p.Pro522fs

c.1563dup · rs786202339 · VCV2091666

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

ultra-rare (gnomAD MAF 2.891e-06)

Conditions

hereditary breast carcinoma

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	escapes	premature termination codon in the last exon (15 of 15) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 6.3	GERP 0.8, phastCons 1
Region caveats
Repeat context	seg dup	· reads may not map uniquely · confidence, not pathogenicity

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

Population frequency

dbSNP / gnomAD

Global frequency 0.000289% via dbSNP · ultra-rare

No ancestry breakdown or filtering allele frequency is available for this variant, so BA1/BS1 cannot be assessed from this figure alone.

Variant & gene context

Gene: CHEK2
Protein: p.Pro522fs
Coding: c.1563dup
MANE Select: NM_007194
dbSNP: rs786202339
Type: Duplication
Location: chr22:28687965 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 522: the 'disordered' region

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

Disease context

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

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

CHEK2 p.Pro522= Conflicting classifications of pathogenicity ★ same residue
CHEK2 p.Pro522Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro522His Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro522Leu Uncertain significance ★ ⚠ same residue
CHEK2 p.Pro522Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Arg431Ter Pathogenic/Likely pathogenic ★★ same condition
CHEK2 p.Asp162fs Pathogenic ★★ same condition
CHEK2 p.Asp203Ter 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-pro522fs (accessed [today's date]).

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