Is CHEK2 p.Ser5= (c.15G>A) pathogenic?

CHEK2 p.Ser5= (c.15G>A) is classified Benign/Likely benign in CHEK2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-01-27). Ultra-rare (popmax 0.033%, sas); Associated with Breast and/or ovarian cancer.

What condition is associated with CHEK2 p.Ser5= (c.15G>A)?

CHEK2 p.Ser5= (c.15G>A) is associated with Breast and/or ovarian cancer, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is CHEK2 p.Ser5= (c.15G>A) in the general population?

CHEK2 p.Ser5= (c.15G>A) is ultra-rare (popmax 0.033%, sas) (gnomAD).

CHEK2 p.Ser5=

c.15G>A · rs145183886 · VCV220067

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.033%, sas)

Conditions

Breast and/or ovarian cancer

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 -6.6	GERP -3.1
Overall
CADD	1.654	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.033% South Asian · 30/91,008 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.00725% 117/1,613,406 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.033%	3,034
East Asian	0.0267%	3,739
African / African-American	0.00935%	10,698
European (non-Finnish)	0.00559%	17,878
Admixed American	0.00167%	59,940
Remaining individualsnot grpmax-eligible	0.0016%	62,498

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.Ser5=
Coding: c.15G>A
MANE Select: NM_007194
dbSNP: rs145183886
Type: single nucleotide variant
Location: chr22:28734707 (GRCh38)
Gene constraint: LOEUF 1.399 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 77.64 · 38 PDB
Residue 5: the 'disordered' region

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 CHEK2-related cancer predisposition

Similar variants

CHEK2 p.Ser5Ter Pathogenic ★ same residue
CHEK2 p.Ser5Ala Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser5Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
CHEK2 p.Ser5Pro Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser5Trp Uncertain significance ★ ⚠ same residue
CHEK2 p.Ser5fs Pathogenic/Likely pathogenic ★★ 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-ser5 (accessed [today's date]).

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