# NM_007194.4(CHEK2):c.1284T>C (p.Ser428=)

https://sugi.bio/variant/chek2-p-ser428

## Summary

**CHEK2 p.Ser428= (c.1284T>C)** is classified **Benign/Likely benign** in CHEK2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-10-07). Very rare (popmax 0.00659%, sas); Associated with hereditary breast carcinoma.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs781514295 · 4 submitters · 2 linked conditions · very rare (popmax 0.00659%, sas)

## For patients & families {#patients}

This is a change in the CHEK2 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 4 submitters, and is linked to hereditary breast carcinoma.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | CHEK2 is a diagnostic-grade gene on 3 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017142/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CHEK2](https://sugi.bio/atlas/gene/CHEK2/) |
| Protein change (HGVS p.) | p.Ser428= |
| Coding change (HGVS c.) | c.1284T>C |
| MANE Select transcript | [NM_007194](https://www.ncbi.nlm.nih.gov/nuccore/NM_007194) |
| dbSNP | [rs781514295](https://www.ncbi.nlm.nih.gov/snp/rs781514295/) |
| Variant type | single nucleotide variant |
| Location | chr22:28695218-28695218 (GRCh38) |
| ClinVar | [VCV479547](https://www.ncbi.nlm.nih.gov/clinvar/variation/479547/) |

**All HGVS expressions:** `LRG_302:g.51649T>C`, `LRG_302t1:c.1284T>C`, `NC_000022.10:g.29091206A>G`, `NC_000022.11:g.28695218A>G`, `NG_008150.2:g.51649T>C`, `NM_001005735.3:c.1413T>C`, `NM_001257387.3:c.621T>C`, `NM_001349956.3:c.1083T>C`, `NM_007194.4:c.1284T>C`, `NM_145862.3:c.1197T>C`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.20) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 4.283, GERP 1.71, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 12.91**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI deltas (raw): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**. Largest is acceptor loss.
- SpliceAI deltas (masked): acceptor loss **0.20**, donor loss **0.00**, acceptor gain **0.03**, donor gain **0.00**.
- Population frequency (gnomAD v4.1): grpmax **0.00659%** (sas) · FAF95 0.00286% · FAF99 0.00195% · 6/91,006 in the highest group · 6/1,611,464 alleles overall — very rare (popmax 0.00659%, sas).

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**CHEK2** population constraint: LOEUF 1.399, pLI 2.847e-14, missense-Z -0.016674; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **CHEK2-related cancer predisposition** — Definitive (AD)
- **familial ovarian cancer** — Refuted (AD)
- **hereditary nonpolyposis colon cancer** — Limited (AD)

## Protein context {#protein}

Residue **428** lies in the protein kinase domain; a UniProt-annotated variant site (may increase breast cancer risk).

AlphaFold model confidence (whole protein): pLDDT 77.64, 49% of residues very-high.

**38 experimental structure(s)** (PDB): [1GXC](https://www.rcsb.org/structure/1GXC), [2CN5](https://www.rcsb.org/structure/2CN5), [2CN8](https://www.rcsb.org/structure/2CN8), [2W0J](https://www.rcsb.org/structure/2W0J), [2W7X](https://www.rcsb.org/structure/2W7X), [2WTC](https://www.rcsb.org/structure/2WTC).

## What this gene does {#gene-function}

*Describes the biological roles of CHEK2 (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** CHEK2's established molecular role includes protein serine/threonine kinase activity. p.Ser428= falls in the protein kinase domain.


### Pathways affected {#pathways}

CHEK2 participates in **8 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex](https://reactome.org/content/detail/R-HSA-75035) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A](https://reactome.org/content/detail/R-HSA-69601) | curated |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine kinase activity, protein kinase binding, ubiquitin protein ligase binding, identical protein binding, protein homodimerization activity.

**Biological process:** G2/M transition of mitotic cell cycle, double-strand break repair, regulation of DNA-templated transcription, protein phosphorylation, DNA damage response, intrinsic apoptotic signaling pathway in response to DNA damage.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-10-07.

**Submitter consensus:** conflicting (3 Likely benign, 1 Benign).

**Submission history:** 4 submissions (2016–2024); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2016-03-11 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2017-08-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-02-17 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-10-07 |

## Associated conditions {#conditions}

[hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Familial cancer of breast, Hereditary cancer-predisposing syndrome, BREAST CANCER, FAMILIAL, Hereditary breast cancer, hereditary breast carcinoma, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **428** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [CHEK2 p.Ser428fs](/variant/chek2-p-ser428fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related CHEK2 variant pages (same residue, condition, or type): [CHEK2 p.Ser428Pro](/variant/chek2-p-ser428pro), [CHEK2 p.Ser428Cys](/variant/chek2-p-ser428cys), [CHEK2 p.Ser428Phe](/variant/chek2-p-ser428phe), [CHEK2 p.Ser428fs](/variant/chek2-p-ser428fs), [CDS1 p.Gln428His](/variant/cds1-p-gln428his), [CHEK2 c.1008+1G>A](/variant/chek2-c-1008-plus-1g-a), [CHEK2 c.1008+1G>T](/variant/chek2-c-1008-plus-1g-t), [CHEK2 c.1008+2T>A](/variant/chek2-c-1008-plus-2t-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 479547). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*