# NM_004360.5(CDH1):c.2398del (p.Arg800fs)

https://sugi.bio/variant/cdh1-p-arg800fs

## Summary

**CDH1 p.Arg800fs (c.2398del)** is classified **Pathogenic** in CDH1 (ClinVar, Expert panel, 7 submitters; last evaluated 2023-08-29). No gnomAD frequency available for this variant; Associated with CDH1-related diffuse gastric and lobular breast cancer syndrome.

**At a glance:** Pathogenic · review: Expert panel · rsID rs587783048 · 7 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the CDH1 gene that is considered disease-causing, submitted by 7 submitters, and is linked to CDH1-related diffuse gastric and lobular breast cancer syndrome.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026244/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [CDH1](https://sugi.bio/atlas/gene/CDH1/) |
| Protein change (HGVS p.) | p.Arg800fs |
| Coding change (HGVS c.) | c.2398del |
| MANE Select transcript | [NM_004360](https://www.ncbi.nlm.nih.gov/nuccore/NM_004360) |
| dbSNP | [rs587783048](https://www.ncbi.nlm.nih.gov/snp/rs587783048/) |
| Variant type | Deletion |
| Location | chr16:68829753-68829753 (GRCh38) |
| ClinVar | [VCV156497](https://www.ncbi.nlm.nih.gov/clinvar/variation/156497/) |

**All HGVS expressions:** `LRG_301:g.97465del`, `LRG_301t1:c.2398del`, `NC_000016.10:g.68829756del`, `NC_000016.9:g.68863659del`, `NG_008021.1:g.97465del`, `NM_001317184.2:c.2215del`, `NM_001317185.2:c.850del`, `NM_001317186.2:c.433del`, `NM_004360.3:c.2398del`, `NM_004360.5:c.2398del`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -2.319, GERP -3.55 — fast-evolving / accelerated position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **within the last 50 nt of the penultimate exon (15 of 16, 44 nt from its 3' end)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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}

**CDH1** population constraint: LOEUF 0.514, pLI 0.85613, missense-Z 1.9041; ClinGen dosage — haploinsufficiency 3, triplosensitivity 0 (0–3 scale). *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):

- **CDH1-related diffuse gastric and lobular breast cancer syndrome** — Definitive (AD)
- **familial ovarian cancer** — No Known Disease Relationship (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.13, 46% of residues very-high.

**22 experimental structure(s)** (PDB): [1O6S](https://www.rcsb.org/structure/1O6S), [2O72](https://www.rcsb.org/structure/2O72), [2OMT](https://www.rcsb.org/structure/2OMT), [2OMU](https://www.rcsb.org/structure/2OMU), [2OMV](https://www.rcsb.org/structure/2OMV), [2OMX](https://www.rcsb.org/structure/2OMX).

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

*Describes the biological roles of CDH1 (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:** CDH1's established molecular role includes beta-catenin binding. In Reactome, CDH1 is annotated in disease pathway(s) including **InlA-mediated entry of Listeria monocytogenes into host cells**.

**Disease mechanism (Reactome):** CDH1 loss or alteration is curated in [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493).

### Pathways affected {#pathways}

CDH1 participates in **19 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [InlA-mediated entry of Listeria monocytogenes into host cells](https://reactome.org/content/detail/R-HSA-8876493) | curated |
| [Adherens junctions interactions](https://reactome.org/content/detail/R-HSA-418990) | curated |
| [Apoptotic cleavage of cell adhesion  proteins](https://reactome.org/content/detail/R-HSA-351906) | curated |
| [Degradation of CDH1](https://reactome.org/content/detail/R-HSA-9766229) | curated |
| [Developmental Lineage of Mammary Gland Luminal Epithelial Cells](https://reactome.org/content/detail/R-HSA-9927418) | curated |
| [Developmental Lineage of Mammary Gland Myoepithelial Cells](https://reactome.org/content/detail/R-HSA-9927432) | curated |
| [Developmental Lineage of Mammary Stem Cells](https://reactome.org/content/detail/R-HSA-9938206) | curated |
| [Integrin cell surface interactions](https://reactome.org/content/detail/R-HSA-216083) | curated |
| [RHO GTPases activate IQGAPs](https://reactome.org/content/detail/R-HSA-5626467) | curated |
| [Regulation of CDH1 Function](https://reactome.org/content/detail/R-HSA-9764561) | curated |
| [Regulation of CDH1 mRNA translation by microRNAs](https://reactome.org/content/detail/R-HSA-9764562) | curated |
| [Regulation of CDH1 posttranslational processing and trafficking to plasma membrane](https://reactome.org/content/detail/R-HSA-9768727) | curated |
| [Regulation of MITF-M-dependent genes involved in extracellular matrix, focal adhesion and epithelial-to-mesenchymal transition](https://reactome.org/content/detail/R-HSA-9926550) | curated |
| [SRC activates STAT3 in a quantitative manner, through Cadherin-11 (CDH11), RAC1 and gp130 (IL6ST)](https://reactome.org/content/detail/R-HSA-9958810) | curated |
| [Transcriptional and post-translational regulation of MITF-M expression and activity](https://reactome.org/content/detail/R-HSA-9856649) | curated |
| [Activation of STAT3 by cadherin engagement](https://reactome.org/content/detail/R-HSA-9958825) | electronic |
| [Degradation of the extracellular matrix](https://reactome.org/content/detail/R-HSA-1474228) | electronic |
| [Formation of definitive endoderm](https://reactome.org/content/detail/R-HSA-9823730) | electronic |
| [Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell](https://reactome.org/content/detail/R-HSA-198933) | electronic |

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

**Molecular function:** beta-catenin binding, ankyrin binding, GTPase activating protein binding, identical protein binding, gamma-catenin binding, cadherin binding.

**Biological process:** desmosome assembly, regulation of gene expression, negative regulation of cell-cell adhesion, negative regulation of cell migration, adherens junction organization, positive regulation of protein import into nucleus.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2023-08-29.

**Submitter consensus:** conflicting (6 Pathogenic, 1 Uncertain significance).

**Submission history:** 7 submissions (2014–2025); classifications have differed over time.

**ClinGen expert panel:** Pathogenic — CDH1 VCEP (CDH1-related diffuse gastric and lobular breast cancer). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PVS1_Strong`, `PM2_Supporting`, `PS4`, `PP1`.
*Considered but not met:* `PM6`, `PS1`, `PS2`, `PS3`, `PM1`, `PP2`, `PP3`, `PP4`, `BS2`, `PM3`, `BS1`, `BS4`, `BS3`, `BP5`, `BP7`, `PM5`, `BP4`, `BP3`, `BP1`, `BP2`, `BA1`, `PM4`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.2398delC (p.Arg800Alafs*16) variant is predicted to result in a premature stop codon that leads to a truncated protein. However, it is located within the nonsense mediated decay resistance region upstream of c.2506G>T (p.Glu836*) (PVS1_Strong). The variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). This variant has been reported in at least 4 families meeting HDGC clinical criteria (PS4; PMID 17545690). This variant was also found to co-segregation with disease in multiple affected family members, with 3 or 4 meioses observed (PP1; PMID: 17545690). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the CDH1 Variant Curation Expert Panel (Variant Interpretation Guidelines Version 3.1): PVS1_Strong, PM2_Supporting, PS4, PP1.
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50014 · approved 2023-08-29 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/a4959b72-3cf7-4e15-96c5-b96fd19dd327).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2024-06-25 |
| Pathway Genomics | Pathogenic | no assertion criteria provided | clinical testing | 2014-07-24 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-03 |
| Clingen Gastric Cancer Variant Curation Expert Panel | Pathogenic | reviewed by expert panel | curation | 2023-08-29 |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-15 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-22 |

## Associated conditions {#conditions}

[CDH1-related diffuse gastric and lobular breast cancer syndrome](https://sugi.bio/atlas/disease/cdh1-related-diffuse-gastric-and-lobular-breast-cancer-syndrome/), [hereditary diffuse gastric adenocarcinoma](https://sugi.bio/atlas/disease/hereditary-diffuse-gastric-adenocarcinoma/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** CDH1-related diffuse gastric and lobular breast cancer syndrome, Hereditary diffuse gastric adenocarcinoma, not provided, Hereditary cancer-predisposing syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, CDH1-related diffuse gastric and lobular breast cancer, DIFFUSE GASTRIC AND LOBULAR BREAST CANCER SYNDROME.

## Similar variants {#similar}

Related CDH1 variant pages (same residue, condition, or type): [CDH1 p.Arg800His](/variant/cdh1-p-arg800his), [CDH1 p.Arg800Cys](/variant/cdh1-p-arg800cys), [CDH1 p.Arg800Leu](/variant/cdh1-p-arg800leu), [CDH1 p.Arg800=](/variant/cdh1-p-arg800), [CDH1 p.Arg800Pro](/variant/cdh1-p-arg800pro), [CDH1 c.1137+1del](/variant/cdh1-c-1137-plus-1del), [CDH1 c.1565+1del](/variant/cdh1-c-1565-plus-1del), [CDH1 c.1711+2_1711+7del](/variant/cdh1-c-1711-plus-2-1711-plus-7del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 156497). 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.*