Is CHEK2 p.Ser428= (c.1284T>C) pathogenic?

CHEK2 p.Ser428= (c.1284T>C) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-07). Very rare (popmax 0.00659%, sas); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Ser428= (c.1284T>C)?

CHEK2 p.Ser428= (c.1284T>C) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Ser428= (c.1284T>C) in the general population?

CHEK2 p.Ser428= (c.1284T>C) is very rare (popmax 0.00659%, sas) (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.Ser428=

c.1284T>C · rs781514295 · VCV479547

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00659%, sas)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation/SpliceAI carries the signal.
Splicing
SpliceAI	Δ0.20	acceptor loss · deltas
Constraint at this position
Conservation	phyloP 4.3	GERP 1.7, phastCons 1
Overall
CADD	12.91	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% South Asian · 6/91,006 alleles

Filtering AF 0.00286% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00195%

Overall 0.000372% 6/1,611,464 alleles · very rare exomes 6/1,459,134 · genomes 0/152,330 · 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.Ser428=
Coding: c.1284T>C
MANE Select: NM_007194
dbSNP: rs781514295
Type: single nucleotide variant
Location: chr22:28695218 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 428: the protein kinase domain; a UniProt-annotated variant site (may increase breast cancer risk)

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

Also linked: hereditary neoplastic syndrome

For Hereditary breast cancer (Orphanet):

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

Similar variants

CHEK2 p.Ser428Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser428Cys Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser428Phe Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ser428fs Pathogenic ★ same residue
CDS1 p.Gln428His Uncertain significance ★ ⚠ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T Likely pathogenic ★★ same condition
CHEK2 c.1008+2T>A 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-ser428 (accessed [today's date]).

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