# NM_007194.4(CHEK2):c.1565C>A (p.Pro522His)

https://sugi.bio/variant/chek2-p-pro522his

## Summary

**CHEK2 p.Pro522His (c.1565C>A)** is classified **Uncertain significance** in CHEK2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-10-22). AlphaMissense: likely benign (0.0987); Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

**At a glance:** Uncertain significance · review: Single submitter · rsID rs2145738801 · 1 submitter · 1 linked condition · AlphaMissense likely benign · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the CHEK2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 1 submitter, 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.Pro522His |
| Coding change (HGVS c.) | c.1565C>A |
| MANE Select transcript | [NM_007194](https://www.ncbi.nlm.nih.gov/nuccore/NM_007194) |
| dbSNP | [rs2145738801](https://www.ncbi.nlm.nih.gov/snp/rs2145738801/) |
| Variant type | single nucleotide variant |
| Location | chr22:28687964-28687964 (GRCh38) |
| ClinVar | [VCV2036435](https://www.ncbi.nlm.nih.gov/clinvar/variation/2036435/) |

**All HGVS expressions:** `LRG_302:g.58903C>A`, `LRG_302t1:c.1565C>A`, `NC_000022.10:g.29083952G>T`, `NC_000022.11:g.28687964G>T`, `NG_008150.2:g.58903C>A`, `NM_001005735.3:c.1694C>A`, `NM_001257387.3:c.902C>A`, `NM_001349956.3:c.1364C>A`, `NM_007194.4:c.1565C>A`, `NM_145862.3:c.1478C>A`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.0987)
- REVEL 0.043 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -8.692 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 1.51, GERP -0.541, phastCons 0.975 — weakly conserved position
- CADD: **PHRED 12.07**. 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.*
- Regional missense constraint: **o/e 1.02** across the covering region of the MANE Select transcript (28,687,900–28,734,721), spanning 46,821 bp. Chi-square p 0.57. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 **522** lies in the 'disordered' region.

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.Pro522His falls in the disordered region.


### 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}

**Uncertain significance** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-10-22.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-10-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial cancer of breast, BREAST CANCER, FAMILIAL, hereditary breast carcinoma, Hereditary breast cancer.

## Similar variants {#similar}

Related CHEK2 variant pages (same residue, condition, or type): [CHEK2 p.Pro522=](/variant/chek2-p-pro522), [CHEK2 p.Pro522Ala](/variant/chek2-p-pro522ala), [CHEK2 p.Pro522Leu](/variant/chek2-p-pro522leu), [CHEK2 p.Pro522Ser](/variant/chek2-p-pro522ser), [CHEK2 p.Pro522fs](/variant/chek2-p-pro522fs), [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 2026-10-06); 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 2036435). 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.*