Is CHEK2 p.Ser67Phe (c.200C>T) pathogenic?

CHEK2 p.Ser67Phe (c.200C>T) is classified Uncertain significance in CHEK2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-17). AlphaMissense: ambiguous (0.4399); Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

What condition is associated with CHEK2 p.Ser67Phe (c.200C>T)?

CHEK2 p.Ser67Phe (c.200C>T) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is CHEK2 p.Ser67Phe (c.200C>T) in the general population?

CHEK2 p.Ser67Phe (c.200C>T) is absent from gnomAD v4.1 (gnomAD).

How is Hereditary breast cancer inherited?

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

What do computational predictors say about CHEK2 p.Ser67Phe (c.200C>T)?

AlphaMissense predicts ambiguous (score 0.4399) — an in-silico prediction, not a clinical call.

CHEK2 p.Ser67Phe

c.200C>T · rs886041171 · VCV566140

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4399 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
AlphaMissense	0.4399	ambiguous
REVEL	0.254	benign-leaning
SaProt	LLR -8.83	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.8	GERP 1.5, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 47 kb · p 0.57 · regional, not allelic
Overall
CADD	26.2	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CHEK2
Protein: p.Ser67Phe
Coding: c.200C>T
MANE Select: NM_007194
dbSNP: rs886041171
Type: single nucleotide variant
Location: chr22:28734522 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB

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.Ser67Ala Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser67Tyr Uncertain significance ★★ ⚠ same residue
CHEK2 p.Ser67= Likely benign ★★ same residue
CHEK2 p.Ser67Thr Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser67fs 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

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-ser67phe (accessed [today's date]).

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