Is CHEK2 p.Glu450Ter (c.1348G>T) pathogenic?

CHEK2 p.Glu450Ter (c.1348G>T) is classified Pathogenic in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-06-28). Very rare (popmax 0.00223%, eas); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Glu450Ter (c.1348G>T)?

CHEK2 p.Glu450Ter (c.1348G>T) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Glu450Ter (c.1348G>T) in the general population?

CHEK2 p.Glu450Ter (c.1348G>T) is very rare (popmax 0.00223%, eas) (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.Glu450Ter

c.1348G>T · rs1555913429 · VCV954385

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 12 of 15
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Pangolin	Δ0.36	loss · gain 0.00 · not in the SpliceAI release · independent
Constraint at this position
Conservation	phyloP 4	GERP 1.7, phastCons 1
Overall
CADD	40.0	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,860 alleles

Overall 6.85e-05% 1/1,460,340 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.Glu450Ter
Coding: c.1348G>T
MANE Select: NM_007194
dbSNP: rs1555913429
Type: single nucleotide variant
Location: chr22:28695154 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 450: an α-helix; the protein kinase domain

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.Glu450Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Glu450Asp Uncertain significance ★ ⚠ same residue
CHEK2 p.Glu450Gln Uncertain significance ★ ⚠ same residue
CHEK2 p.Glu450fs Pathogenic ★ same residue
CHEK2 p.Glu450= Likely benign ★ same residue
CHEK2 p.Glu450Lys Uncertain significance ⚠ same residue
CHEK2 c.1008+1G>A Likely pathogenic ★★ same condition
CHEK2 c.1008+1G>T 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-glu450ter (accessed [today's date]).

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