# NM_000251.3(MSH2):c.1314_1315dup (p.Pro439fs)

https://sugi.bio/variant/msh2-p-pro439fs

## Summary

**MSH2 p.Pro439fs (c.1314_1315dup)** is classified **Pathogenic** in MSH2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). Associated with Hereditary nonpolyposis colorectal neoplasms.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the MSH2 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, and is linked to Hereditary nonpolyposis colorectal neoplasms.

*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:** [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [MSH2](https://sugi.bio/atlas/gene/MSH2/) |
| Protein change (HGVS p.) | p.Pro439fs |
| Coding change (HGVS c.) | c.1314_1315dup |
| MANE Select transcript | [NM_000251](https://www.ncbi.nlm.nih.gov/nuccore/NM_000251) |
| Variant type | Duplication |
| Location | chr2:47445583-47445584 (GRCh38) |
| ClinVar | [VCV3729155](https://www.ncbi.nlm.nih.gov/clinvar/variation/3729155/) |

**All HGVS expressions:** `LRG_218:g.47462_47463dup`, `LRG_218t1:c.1314_1315dup`, `NC_000002.11:g.47672724_47672725dup`, `NC_000002.12:g.47445585_47445586dup`, `NG_007110.2:g.47462_47463dup`, `NM_000251.3:c.1314_1315dup`, `NM_001258281.1:c.1116_1117dup`, `NM_001406631.1:c.1314_1315dup`, `NM_001406632.1:c.1314_1315dup`, `NM_001406633.1:c.1314_1315dup`, `NM_001406634.1:c.1314_1315dup`, `NM_001406635.1:c.1314_1315dup`, `NM_001406636.1:c.1281_1282dup`, `NM_001406637.1:c.1314_1315dup`, `NM_001406638.1:c.1314_1315dup`, `NM_001406639.1:c.1314_1315dup`, `NM_001406640.1:c.1314_1315dup`, `NM_001406641.1:c.1314_1315dup`, `NM_001406642.1:c.1314_1315dup`, `NM_001406643.1:c.1314_1315dup`, `NM_001406644.1:c.1314_1315dup`, `NM_001406645.1:c.1314_1315dup`, `NM_001406646.1:c.1314_1315dup`, `NM_001406647.1:c.1164_1165dup`, `NM_001406648.1:c.1314_1315dup`, `NM_001406649.1:c.1164_1165dup`, `NM_001406650.1:c.1164_1165dup`, `NM_001406651.1:c.1164_1165dup`, `NM_001406652.1:c.1164_1165dup`, `NM_001406653.1:c.1254_1255dup`, `NM_001406654.1:c.894_895dup`, `NM_001406655.1:c.1314_1315dup`, `NM_001406656.1:c.417_418dup`, `NM_001406657.1:c.1314_1315dup`, `NM_001406658.1:c.-43_-42dup`, `NM_001406659.1:c.-43_-42dup`, `NM_001406660.1:c.-43_-42dup`, `NM_001406661.1:c.-43_-42dup`, `NM_001406662.1:c.-43_-42dup`, `NM_001406666.1:c.1314_1315dup`, `NM_001406669.1:c.-43_-42dup`, `NM_001406672.1:c.1164_1165dup`, `NM_001406674.1:c.1314_1315dup`, `NR_176230.1:n.1350_1351dup`, `NR_176231.1:n.1350_1351dup`, `NR_176232.1:n.1350_1351dup`, `NR_176233.1:n.1192_1193dup`, `NR_176234.1:n.1350_1351dup`, `NR_176235.1:n.1350_1351dup`, `NR_176236.1:n.1350_1351dup`, `NR_176237.1:n.1350_1351dup`, `NR_176238.1:n.1350_1351dup`, `NR_176239.1:n.1350_1351dup`, `NR_176240.1:n.1350_1351dup`, `NR_176241.1:n.1350_1351dup`, `NR_176242.1:n.1350_1351dup`, `NR_176243.1:n.1200_1201dup`, `NR_176244.1:n.1350_1351dup`, `NR_176245.1:n.1350_1351dup`, `NR_176246.1:n.1350_1351dup`, `NR_176247.1:n.1350_1351dup`, `NR_176248.1:n.1350_1351dup`, `NR_176249.1:n.1580_1581dup`

## 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 5.807, GERP 0.642, phastCons 1 — highly conserved position (PP3-type support)
- 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 **in exon 8 of 16**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no duplication variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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}

**MSH2** population constraint: LOEUF 0.672, pLI 4.5659e-06, missense-Z -2.8782; 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):

- **Lynch syndrome** — Definitive (AD)
- **mismatch repair cancer syndrome 1** — Definitive (AR)
- **hereditary breast carcinoma** — Refuted (AD)

## Protein context {#protein}

Residue **439** lies in an α-helix.

AlphaFold model confidence (whole protein): pLDDT 85.60, 46% of residues very-high.

**30 experimental structure(s)** (PDB): [2O8B](https://www.rcsb.org/structure/2O8B), [2O8C](https://www.rcsb.org/structure/2O8C), [2O8D](https://www.rcsb.org/structure/2O8D), [2O8E](https://www.rcsb.org/structure/2O8E), [2O8F](https://www.rcsb.org/structure/2O8F), [3THW](https://www.rcsb.org/structure/3THW).

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

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

**Disease mechanism (Reactome):** MSH2 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), [Defective Mismatch Repair Associated With MSH6](https://reactome.org/content/detail/R-HSA-5632968).

### Pathways affected {#pathways}

MSH2 participates in **7 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 |
| ⚕ [Defective Mismatch Repair Associated With MSH6](https://reactome.org/content/detail/R-HSA-5632968) | curated |
| [Mismatch repair (MMR) directed by MSH2:MSH6 (MutSalpha)](https://reactome.org/content/detail/R-HSA-5358565) | curated |
| [Somatic hypermutation of immunoglobulin genes by error-prone mismatch repair (MMR)](https://reactome.org/content/detail/R-HSA-9968295) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | 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:** DNA binding, chromatin binding, enzyme activator activity, ATP-dependent activity, acting on DNA, guanine/thymine mispair binding, protein homodimerization activity.

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

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-04-02.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-04-02 |

## Associated conditions {#conditions}

[Hereditary nonpolyposis colorectal neoplasms](https://sugi.bio/atlas/disease/hereditary-nonpolyposis-colorectal-neoplasms/).

**Reported phenotype names (ClinVar):** Hereditary nonpolyposis colorectal neoplasms.

## Same-residue context {#hotspot}

Residue **439** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MSH2 p.Pro439_Asp442del](/variant/msh2-p-pro439-asp442del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MSH2 variant pages (same residue, condition, or type): [MSH2 p.Pro439_Asp442del](/variant/msh2-p-pro439-asp442del), [MSH2 p.Pro439Arg](/variant/msh2-p-pro439arg), [MSH2 p.Pro439Thr](/variant/msh2-p-pro439thr), [MSH2 c.1076+1dup](/variant/msh2-c-1076-plus-1dup), [MSH2 p.Ala305fs](/variant/msh2-p-ala305fs), [MSH2 p.Arg219fs](/variant/msh2-p-arg219fs), [MSH2 p.Asp386fs](/variant/msh2-p-asp386fs), [MSH2 p.Asp442Ter](/variant/msh2-p-asp442ter).

### 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 3729155). 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.*