Is CHEK2 p.Leu280= (c.838C>T) pathogenic?

CHEK2 p.Leu280= (c.838C>T) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-10-03). Very rare (popmax 0.00225%, sas); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Leu280= (c.838C>T)?

CHEK2 p.Leu280= (c.838C>T) is associated with hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Leu280= (c.838C>T) in the general population?

CHEK2 p.Leu280= (c.838C>T) is very rare (popmax 0.00225%, 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.Leu280=

c.838C>T · rs2145932680 · VCV1664029

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00225%, sas)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.72 · evaluated, not missing
Constraint at this position
Conservation	phyloP 3.7	GERP 0.67, phastCons 1
Overall
CADD	9.518	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00225% South Asian · 2/89,068 alleles

Filtering AF 0.000373% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00014%

Overall 0.000218% 3/1,378,386 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00225%	44,534
European (non-Finnish)	9.04e-05%	1,106,504

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.Leu280=
Coding: c.838C>T
MANE Select: NM_007194
dbSNP: rs2145932680
Type: single nucleotide variant
Location: chr22:28710014 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 280: 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.Leu280Arg Uncertain significance ★★ ⚠ same residue
CHEK2 p.Leu280Gln Uncertain significance ★★ ⚠ same residue
CHEK2 p.Leu280Pro Uncertain significance ★★ ⚠ same residue
CHEK2 p.Leu280_Asn281insLeu 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
CHEK2 c.1008+2T>G 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-leu280 (accessed [today's date]).

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