Is CHEK2 p.Ile157= (c.471T>C) pathogenic?

CHEK2 p.Ile157= (c.471T>C) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2026-01-06). Very rare (popmax 0.00144%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Ile157= (c.471T>C)?

CHEK2 p.Ile157= (c.471T>C) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Ile157= (c.471T>C) in the general population?

CHEK2 p.Ile157= (c.471T>C) is very rare (popmax 0.00144%, nfe) (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.Ile157=

c.471T>C · rs374170772 · VCV183809

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00144%, nfe)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.063	GERP -1.3, phastCons 0.17
Overall
CADD	6.672	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00144% European (non-Finnish) · 17/1,180,018 alleles

Filtering AF 0.000878% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000717%

Overall 0.00123% 18/1,461,836 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,506
European (non-Finnish)grpmax	0.00144%	69,413

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ile157=
Coding: c.471T>C
MANE Select: NM_007194
dbSNP: rs374170772
Type: single nucleotide variant
Location: chr22:28725098 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 157: the fha domain; a UniProt-annotated variant site (might influence susceptibility to different types of cancer; loss of the ability to interact with and phosphorylate cdc25a and to promote cdc25a degradation in response to ionizing radiation); a β-strand

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.Ile157Asn Uncertain significance ★ ⚠ same residue
CHEK2 p.Ile157Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ile157Val Uncertain significance ★ ⚠ same residue
CHEK2 p.Ile157fs Pathogenic ★ 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-ile157 (accessed [today's date]).

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