# NM_000251.3(MSH2):c.1854A>G (p.Pro618=)

https://sugi.bio/variant/msh2-p-pro618

## Summary

**MSH2 p.Pro618= (c.1854A>G)** is classified **Conflicting classifications of pathogenicity** in MSH2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2025-12-08). Very rare (popmax 0.00446%, eas); Associated with Lynch syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs786203744 · 9 submitters · 3 linked conditions · very rare (popmax 0.00446%, eas)

## 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 9 submitters, and is linked to Lynch 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult |
| Clinical trials | 106 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | MSH2 is a diagnostic-grade gene on 30 Genomics England panels |

**Commonly reported features of Lynch syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Weight loss — Very frequent (99-80%)
- Constipation — Very frequent (99-80%)
- Malabsorption — Very frequent (99-80%)
- Abdominal pain — Very frequent (99-80%)
- Gastrointestinal hemorrhage — Very frequent (99-80%)
- Neoplasm of the skin — Very frequent (99-80%)
- Adenoma sebaceum — Very frequent (99-80%)
- Glioblastoma multiforme — Very frequent (99-80%)

**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.Pro618= |
| Coding change (HGVS c.) | c.1854A>G |
| MANE Select transcript | [NM_000251](https://www.ncbi.nlm.nih.gov/nuccore/NM_000251) |
| dbSNP | [rs786203744](https://www.ncbi.nlm.nih.gov/snp/rs786203744/) |
| Variant type | single nucleotide variant |
| Location | chr2:47475119-47475119 (GRCh38) |
| ClinVar | [VCV187451](https://www.ncbi.nlm.nih.gov/clinvar/variation/187451/) |

**All HGVS expressions:** `LRG_218:g.76996A>G`, `LRG_218t1:c.1854A>G`, `NC_000002.11:g.47702258A>G`, `NC_000002.12:g.47475119A>G`, `NG_007110.2:g.76996A>G`, `NM_000251.3:c.1854A>G`, `NM_001258281.1:c.1656A>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 (below), not from a missing predictor score.
- Conservation: phyloP -5.101, GERP -3.65 — fast-evolving / accelerated position
- CADD: **PHRED 0.395**. 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: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for MSH2 (829 scored positions, the nearest 3 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **0.00446%** (eas) · FAF95 0.00106% · FAF99 0.000605% · 2/44,886 in the highest group · 20/1,614,074 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,443 |
| African / African-American | 0.004% | 24,977 |
| European (non-Finnish) | 0.00127% | 78,671 |

*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 **618** lies in the 'interaction with exo1' region.

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. p.Pro618= falls in the interaction with exo1 region. 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 2025-12-08.

**Submitter consensus:** conflicting (6 Likely benign, 1 Benign, 1 Likely Benign, 1 Uncertain significance).

**Submission history:** 9 submissions (2015–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2015-07-24 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2018-07-16 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2023-03-17 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Likely benign | criteria provided, single submitter | clinical testing | 2024-06-22 |
| Counsyl | Likely benign | no assertion criteria provided | clinical testing | 2017-12-22 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-08 |
| All of Us Research Program, National Institutes of Health | Likely Benign | criteria provided, single submitter | clinical testing | 2023-12-13 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-25 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-11-17 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Lynch syndrome, Hereditary cancer-predisposing syndrome, Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 1, not provided, not specified, AllHighlyPenetrant, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **618** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [MSH2 p.Pro618fs](/variant/msh2-p-pro618fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related MSH2 variant pages (same residue, condition, or type): [MSH2 p.Pro618Ala](/variant/msh2-p-pro618ala), [MSH2 p.Pro618Leu](/variant/msh2-p-pro618leu), [MSH2 p.Pro618Ser](/variant/msh2-p-pro618ser), [MSH2 p.Pro618fs](/variant/msh2-p-pro618fs), [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).

### 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 187451). 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.*