# NM_000251.3(MSH2):c.2256A>G (p.Arg752=)

https://sugi.bio/variant/msh2-p-arg752

## Summary

**MSH2 p.Arg752= (c.2256A>G)** is classified **Conflicting classifications of pathogenicity** in MSH2 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-10-16). Very rare (popmax 8.47e-05%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · 2 submitters · 2 linked conditions · very rare (popmax 8.47e-05%, nfe)

## For patients & families {#patients}

This is a change in the MSH2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 2 submitters, and is linked to hereditary neoplastic 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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [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.Arg752= |
| Coding change (HGVS c.) | c.2256A>G |
| MANE Select transcript | [NM_000251](https://www.ncbi.nlm.nih.gov/nuccore/NM_000251) |
| Variant type | single nucleotide variant |
| Location | chr2:47478317-47478317 (GRCh38) |
| ClinVar | [VCV3773361](https://www.ncbi.nlm.nih.gov/clinvar/variation/3773361/) |

**All HGVS expressions:** `LRG_218:g.80194A>G`, `LRG_218t1:c.2256A>G`, `NC_000002.11:g.47705456A>G`, `NC_000002.12:g.47478317A>G`, `NG_007110.2:g.80194A>G`, `NM_000251.1:c.2256A>G`, `NM_000251.3:c.2256A>G`, `NM_001258281.1:c.2058A>G`, `NM_001406631.1:c.2256A>G`, `NM_001406632.1:c.2256A>G`, `NM_001406633.1:c.2256A>G`, `NM_001406634.1:c.2256A>G`, `NM_001406635.1:c.2256A>G`, `NM_001406636.1:c.2223A>G`, `NM_001406637.1:c.2256A>G`, `NM_001406638.1:c.2295A>G`, `NM_001406639.1:c.2256A>G`, `NM_001406640.1:c.2256A>G`, `NM_001406641.1:c.2256A>G`, `NM_001406642.1:c.2256A>G`, `NM_001406643.1:c.2256A>G`, `NM_001406644.1:c.2256A>G`, `NM_001406645.1:c.2256A>G`, `NM_001406646.1:c.2256A>G`, `NM_001406647.1:c.2106A>G`, `NM_001406648.1:c.2256A>G`, `NM_001406649.1:c.2106A>G`, `NM_001406650.1:c.2106A>G`, `NM_001406651.1:c.2106A>G`, `NM_001406652.1:c.2106A>G`, `NM_001406653.1:c.2196A>G`, `NM_001406654.1:c.1836A>G`, `NM_001406656.1:c.1359A>G`, `NM_001406658.1:c.900A>G`, `NM_001406659.1:c.900A>G`, `NM_001406660.1:c.900A>G`, `NM_001406661.1:c.900A>G`, `NM_001406662.1:c.900A>G`, `NM_001406669.1:c.900A>G`, `NM_001406674.1:c.2256A>G`, `NR_176230.1:n.2292A>G`, `NR_176231.1:n.2260A>G`, `NR_176232.1:n.2292A>G`, `NR_176233.1:n.2134A>G`, `NR_176234.1:n.2292A>G`, `NR_176235.1:n.2292A>G`, `NR_176236.1:n.2292A>G`, `NR_176237.1:n.2292A>G`, `NR_176238.1:n.2425A>G`, `NR_176239.1:n.2292A>G`, `NR_176240.1:n.2087A>G`, `NR_176241.1:n.2292A>G`, `NR_176242.1:n.2292A>G`, `NR_176243.1:n.2142A>G`, `NR_176244.1:n.2292A>G`, `NR_176245.1:n.2292A>G`, `NR_176246.1:n.2292A>G`, `NR_176247.1:n.2292A>G`, `NR_176248.1:n.2292A>G`, `NR_176249.1:n.2522A>G`, `NR_176250.1:n.2032A>G`

## 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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **acceptor loss** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 3.605, GERP -1.79, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 5.806**. 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 deltas (raw): acceptor loss **0.22**, donor loss **0.04**, acceptor gain **0.00**, donor gain **0.00**. Largest is acceptor loss, 45 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Pangolin: Δ**0.25** (loss), gain 0.00 / loss 0.25. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **8.47e-05%** (nfe) · 1/1,179,950 in the highest group · 1/1,614,110 alleles overall — very rare (popmax 8.47e-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}

**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 **752** lies in a turn.

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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-10-16.

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

**Submission history:** 2 submissions (2024–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-12-12 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-16 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Lynch syndrome 1](https://sugi.bio/atlas/disease/lynch-syndrome-1/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Lynch syndrome 1, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Colorectal cancer, hereditary, nonpolyposis, type 1, Hereditary non-polyposis colorectal cancer, type 1, MSH2-Related Hereditary Non-Polyposis Colon Cancer, Lynch syndrome I.

## Same-residue context {#hotspot}

Residue **752** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [MSH2 p.Arg752fs](/variant/msh2-p-arg752fs), [MSH2 p.Arg752Ter](/variant/msh2-p-arg752ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MSH2 variant pages (same residue, condition, or type): [MSH2 p.Arg752Ter](/variant/msh2-p-arg752ter), [MSH2 p.Arg752Lys](/variant/msh2-p-arg752lys), [MSH2 c.1076+1G>A](/variant/msh2-c-1076-plus-1g-a), [MSH2 c.1076+1G>T](/variant/msh2-c-1076-plus-1g-t), [MSH2 c.1077-1G>C](/variant/msh2-c-1077-minus-1g-c), [MSH2 c.1077-1G>T](/variant/msh2-c-1077-minus-1g-t), [MSH2 c.1077-2A>C](/variant/msh2-c-1077-minus-2a-c), [MSH2 c.1077-2A>G](/variant/msh2-c-1077-minus-2a-g).

### 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 3773361). 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.*