Is CHEK2 p.Tyr327= (c.981T>C) pathogenic?

CHEK2 p.Tyr327= (c.981T>C) is classified Likely benign in CHEK2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-04-24). Very rare (popmax 0.0011%, sas); Associated with Breast and/or ovarian cancer.

What condition is associated with CHEK2 p.Tyr327= (c.981T>C)?

CHEK2 p.Tyr327= (c.981T>C) is associated with Breast and/or ovarian cancer, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Tyr327= (c.981T>C) in the general population?

CHEK2 p.Tyr327= (c.981T>C) is very rare (popmax 0.0011%, sas) (gnomAD).

CHEK2 p.Tyr327=

c.981T>C · rs1601738446 · VCV700364

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Conditions

Breast and/or ovarian cancer

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.206	benign-leaning
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.86	GERP -2.3, phastCons 0.97
Overall
CADD	5.112	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,084 alleles

Overall 6.2e-05% 1/1,614,028 alleles · very rare exomes 1/1,461,718 · genomes 0/152,310 · 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.Tyr327=
Coding: c.981T>C
MANE Select: NM_007194
dbSNP: rs1601738446
Type: single nucleotide variant
Location: chr22:28699865 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 327: an α-helix; the protein kinase domain; a UniProt-annotated variant site (in prostate cancer; uncertain significance; somatic mutation)

Full CHEK2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Breast and/or ovarian cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

CHEK2 p.Tyr327Asn Uncertain significance ★★ ⚠ same residue
CHEK2 p.Tyr327Cys Uncertain significance ★★ ⚠ same residue
CHEK2 p.Tyr327Ter Pathogenic ★ same residue
CHEK2 p.Tyr327Phe Uncertain significance ★ ⚠ same residue
CHEK2 p.Tyr327fs 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-tyr327 (accessed [today's date]).

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