# NM_002439.5(MSH3):c.2293_2294insT (p.Pro765fs)

https://sugi.bio/variant/msh3-p-pro765fs

## Summary

**MSH3 p.Pro765fs (c.2293_2294insT)** is classified **Pathogenic** in MSH3 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-08-30). Very rare (popmax 8.64e-05%, nfe); Associated with familial adenomatous polyposis 4.

**At a glance:** Pathogenic · review: Multiple submitters · rsID rs1744286516 · 2 submitters · 1 linked condition · very rare (popmax 8.64e-05%, nfe)

## For patients & families {#patients}

This is a change in the MSH3 gene that is considered disease-causing, submitted by 2 submitters, and is linked to familial adenomatous polyposis 4.

*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 recessive |
| Age of onset (of this condition) | Neonatal |

**Commonly reported features of MSH3-related polyposis** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Juvenile gastrointestinal polyposis — Very frequent (99-80%)
- Adenomatous colonic polyposis — Very frequent (99-80%)
- Colorectal polyposis — Very frequent (99-80%)
- Uterine leiomyoma — Frequent (79-30%)
- Thyroid adenoma — Frequent (79-30%)
- Colon cancer — Frequent (79-30%)
- Multiple gastric polyps — Frequent (79-30%)
- Neoplasm of the skin — Frequent (79-30%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017868/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MSH3](https://sugi.bio/atlas/gene/MSH3/) |
| Protein change (HGVS p.) | p.Pro765fs |
| Coding change (HGVS c.) | c.2293_2294insT |
| MANE Select transcript | [NM_002439](https://www.ncbi.nlm.nih.gov/nuccore/NM_002439) |
| dbSNP | [rs1744286516](https://www.ncbi.nlm.nih.gov/snp/rs1744286516/) |
| Variant type | Insertion |
| Location | chr5:80775733-80775734 (GRCh38) |
| ClinVar | [VCV2673542](https://www.ncbi.nlm.nih.gov/clinvar/variation/2673542/) |

**All HGVS expressions:** `NC_000005.10:g.80775733_80775734insT`, `NC_000005.9:g.80071552_80071553insT`, `NG_016607.2:g.126259_126260insT`, `NM_002439.5:c.2293_2294insT`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 7.604, GERP 1.89, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. Gene population constraint: LOEUF 1.027, pLI 1.3015e-21. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 16 of 24**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 34.0**. 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: **not assessed** — the release is built from a substitutions-only source, so it holds no insertion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **8.64e-05%** (nfe) · 1/1,157,040 in the highest group · 1/1,588,172 alleles overall — very rare (popmax 8.64e-05%, nfe).

*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}

**MSH3** population constraint: LOEUF 1.027, pLI 1.3015e-21, missense-Z -0.48793. *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):

- **familial adenomatous polyposis 4** — Definitive (AR)
- **Lynch syndrome** — Disputed (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 79.48, 61% of residues very-high.

**25 experimental structure(s)** (PDB): [3THW](https://www.rcsb.org/structure/3THW), [3THX](https://www.rcsb.org/structure/3THX), [3THY](https://www.rcsb.org/structure/3THY), [3THZ](https://www.rcsb.org/structure/3THZ), [8OLX](https://www.rcsb.org/structure/8OLX), [8OM5](https://www.rcsb.org/structure/8OM5).

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

*Describes the biological roles of MSH3 (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:** MSH3's established molecular role includes enzyme binding. In Reactome, MSH3 is annotated in disease pathway(s) including **Defective Mismatch Repair Associated With MSH2**, **Defective Mismatch Repair Associated With MSH3**.

**Disease mechanism (Reactome):** MSH3 loss or alteration is curated in [Defective Mismatch Repair Associated With MSH2](https://reactome.org/content/detail/R-HSA-5632928), [Defective Mismatch Repair Associated With MSH3](https://reactome.org/content/detail/R-HSA-5632927).

### Pathways affected {#pathways}

MSH3 participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Mismatch Repair Associated With MSH2](https://reactome.org/content/detail/R-HSA-5632928) | curated |
| ⚕ [Defective Mismatch Repair Associated With MSH3](https://reactome.org/content/detail/R-HSA-5632927) | curated |
| [Mismatch repair (MMR) directed by MSH2:MSH3 (MutSbeta)](https://reactome.org/content/detail/R-HSA-5358606) | electronic |

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

**Molecular function:** enzyme binding.

**Biological process:** DNA repair, mismatch repair, maintenance of DNA repeat elements, negative regulation of DNA recombination.

## Clinical significance {#significance}

**Pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-08-30.

**Submitter consensus:** unanimous (2/2 Pathogenic).

**Submission history:** 2 submissions (2022–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-12-14 |

## Associated conditions {#conditions}

[familial adenomatous polyposis 4](https://sugi.bio/atlas/disease/familial-adenomatous-polyposis-4/).

**Reported phenotype names (ClinVar):** Familial adenomatous polyposis 4, not provided, MSH3-related attenuated familial adenomatous polyposis, none provided.

## Similar variants {#similar}

Related MSH3 variant pages (same residue, condition, or type): [MSH3 p.Glu437fs](/variant/msh3-p-glu437fs), [MSH3 p.Ser490fs](/variant/msh3-p-ser490fs), [MSH3 p.Pro765Ser](/variant/msh3-p-pro765ser), [MSH3 c.2253_2253+1insAT](/variant/msh3-c-2253-2253-plus-1insat), [MSH3 p.Ser570fs](/variant/msh3-p-ser570fs), [MSH3 p.Pro765Arg](/variant/msh3-p-pro765arg), [MSH3 p.Pro765Thr](/variant/msh3-p-pro765thr), [MSH3 c.1341-2A>G](/variant/msh3-c-1341-minus-2a-g).

### 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 2673542). 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.*