# NM_000251.3(MSH2):c.1339_1340del (p.Phe447fs)

https://sugi.bio/variant/msh2-p-phe447fs

## Summary

**MSH2 p.Phe447fs (c.1339_1340del)** is classified **Pathogenic/Likely pathogenic** in MSH2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-08-01). No gnomAD frequency available for this variant; Associated with Hereditary nonpolyposis colorectal neoplasms.

**At a glance:** Pathogenic/Likely pathogenic · review: Multiple submitters · rsID rs1553361231 · 3 submitters · 2 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the MSH2 gene that is considered likely disease-causing, submitted by 3 submitters, 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.Phe447fs |
| Coding change (HGVS c.) | c.1339_1340del |
| MANE Select transcript | [NM_000251](https://www.ncbi.nlm.nih.gov/nuccore/NM_000251) |
| dbSNP | [rs1553361231](https://www.ncbi.nlm.nih.gov/snp/rs1553361231/) |
| Variant type | Deletion |
| Location | chr2:47445610-47445611 (GRCh38) |
| ClinVar | [VCV525597](https://www.ncbi.nlm.nih.gov/clinvar/variation/525597/) |

**All HGVS expressions:** `LRG_218:g.47487_47488del`, `NC_000002.11:g.47672749_47672750del`, `NC_000002.12:g.47445610_47445611del`, `NG_007110.2:g.47487_47488del`, `NM_000251.2:c.1339_1340delTT`, `NM_000251.3:c.1339_1340del`, `NM_001258281.1:c.1141_1142del`

## 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 0.831, GERP 0.562, phastCons 1 — weakly conserved 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 **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 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}

**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 **447** 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/Likely pathogenic** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-08-01.

**Submitter consensus:** conflicting (2 Pathogenic, 1 Likely pathogenic).

**Submission history:** 3 submissions (2017–2023); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Pathogenic | criteria provided, single submitter | clinical testing | 2023-08-01 |
| Baylor Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2021-11-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2017-11-23 |

## Associated conditions {#conditions}

[Hereditary nonpolyposis colorectal neoplasms](https://sugi.bio/atlas/disease/hereditary-nonpolyposis-colorectal-neoplasms/), [Lynch syndrome 1](https://sugi.bio/atlas/disease/lynch-syndrome-1/).

**Reported phenotype names (ClinVar):** Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, Colorectal cancer, hereditary, nonpolyposis, type 1, Hereditary non-polyposis colorectal cancer, type 1, MSH2-Related Lynch Syndrome, COLON CANCER, FAMILIAL NONPOLYPOSIS, TYPE 1, MSH2-Related Hereditary Non-Polyposis Colon Cancer, Lynch syndrome I.

## Similar variants {#similar}

Related MSH2 variant pages (same residue, condition, or type): [MSH2 p.Phe447Val](/variant/msh2-p-phe447val), [MSH2 p.Phe447=](/variant/msh2-p-phe447), [MSH2 p.Phe447Leu](/variant/msh2-p-phe447leu), [MSH2 c.1277-4076_1386+1819del](/variant/msh2-c-1277-minus-4076-1386-plus-1819del), [MSH2 c.1277-6224_1386+4836del](/variant/msh2-c-1277-minus-6224-1386-plus-4836del), [MSH2 c.1277-6284_1386+4776del](/variant/msh2-c-1277-minus-6284-1386-plus-4776del), [MSH2 c.2005+2del](/variant/msh2-c-2005-plus-2del), [MSH2 c.942+2del](/variant/msh2-c-942-plus-2del).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 525597). 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.*