# NM_000535.7(PMS2):c.1353G>A (p.Arg451=)

https://sugi.bio/variant/pms2-p-arg451

## Summary

**PMS2 p.Arg451= (c.1353G>A)** is classified **Uncertain significance** in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-12-18). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · 4 submitters · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the PMS2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 4 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 | [PMS2](https://sugi.bio/atlas/gene/PMS2/) |
| Protein change (HGVS p.) | p.Arg451= |
| Coding change (HGVS c.) | c.1353G>A |
| MANE Select transcript | [NM_000535](https://www.ncbi.nlm.nih.gov/nuccore/NM_000535) |
| Variant type | single nucleotide variant |
| Location | chr7:5987412-5987412 (GRCh38) |
| ClinVar | [VCV3387512](https://www.ncbi.nlm.nih.gov/clinvar/variation/3387512/) |

**All HGVS expressions:** `LRG_161:g.26695G>A`, `LRG_161t1:c.1353G>A`, `NC_000007.13:g.6027043C>T`, `NC_000007.14:g.5987412C>T`, `NG_008466.1:g.26695G>A`, `NM_000535.7:c.1353G>A`, `NM_001322003.2:c.948G>A`, `NM_001322004.2:c.948G>A`, `NM_001322005.2:c.948G>A`, `NM_001322006.2:c.1197G>A`, `NM_001322007.2:c.1035G>A`, `NM_001322008.2:c.1035G>A`, `NM_001322009.2:c.948G>A`, `NM_001322010.2:c.792G>A`, `NM_001322011.2:c.420G>A`, `NM_001322012.2:c.420G>A`, `NM_001322013.2:c.780G>A`, `NM_001322014.2:c.1353G>A`, `NM_001322015.2:c.1044G>A`, `NM_001406866.1:c.1539G>A`, `NM_001406868.1:c.1377G>A`, `NM_001406869.1:c.1245G>A`, `NM_001406870.1:c.1197G>A`, `NM_001406871.1:c.1353G>A`, `NM_001406872.1:c.1353G>A`, `NM_001406873.1:c.1155G>A`, `NM_001406874.1:c.1185G>A`, `NM_001406875.1:c.1044G>A`, `NM_001406876.1:c.1035G>A`, `NM_001406877.1:c.1044G>A`, `NM_001406878.1:c.1044G>A`, `NM_001406879.1:c.1044G>A`, `NM_001406880.1:c.1044G>A`, `NM_001406881.1:c.1044G>A`, `NM_001406882.1:c.1044G>A`, `NM_001406883.1:c.1035G>A`, `NM_001406884.1:c.1029G>A`, `NM_001406885.1:c.1017G>A`, `NM_001406886.1:c.987G>A`, `NM_001406887.1:c.948G>A`, `NM_001406888.1:c.948G>A`, `NM_001406889.1:c.948G>A`, `NM_001406890.1:c.948G>A`, `NM_001406891.1:c.948G>A`, `NM_001406892.1:c.948G>A`, `NM_001406893.1:c.948G>A`, `NM_001406894.1:c.948G>A`, `NM_001406895.1:c.948G>A`, `NM_001406896.1:c.948G>A`, `NM_001406897.1:c.948G>A`, `NM_001406898.1:c.948G>A`, `NM_001406899.1:c.948G>A`, `NM_001406900.1:c.888G>A`, `NM_001406901.1:c.879G>A`, `NM_001406902.1:c.879G>A`, `NM_001406903.1:c.1035G>A`, `NM_001406904.1:c.840G>A`, `NM_001406905.1:c.840G>A`, `NM_001406906.1:c.792G>A`, `NM_001406907.1:c.792G>A`, `NM_001406908.1:c.948G>A`, `NM_001406909.1:c.780G>A`, `NM_001406910.1:c.948G>A`, `NM_001406911.1:c.582G>A`, `NM_001406912.1:c.804-4421G>A`, `NR_136154.1:n.1440G>A`

## 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 **donor gain** (Δ 0.23) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP -0.838 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 5.591**. 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 **0.00**, donor loss **0.01**, acceptor gain **0.00**, donor gain **0.23**. Largest is donor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.23**.
- Pangolin: Δ**0.39** (gain), gain 0.39 / loss 0.00. 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: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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}

**PMS2** population constraint: LOEUF 0.898, pLI 5.3905e-09, missense-Z 0.36886; 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)
- **hereditary breast carcinoma** — Disputed (AD)
- **mismatch repair cancer syndrome 1** — Definitive (AR)

## Protein context {#protein}

Residue **451** lies in the 'disordered' region.

AlphaFold model confidence (whole protein): pLDDT 71.37, 36% of residues very-high.

**9 experimental structure(s)** (PDB): [1EA6](https://www.rcsb.org/structure/1EA6), [1H7S](https://www.rcsb.org/structure/1H7S), [1H7U](https://www.rcsb.org/structure/1H7U), [5U5R](https://www.rcsb.org/structure/5U5R), [6MFQ](https://www.rcsb.org/structure/6MFQ), [7RCB](https://www.rcsb.org/structure/7RCB) — incl. mutant structure 6MFQ.

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

*Describes the biological roles of PMS2 (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:** PMS2's established molecular role includes DNA binding. p.Arg451= falls in the disordered region. In Reactome, PMS2 is annotated in disease pathway(s) including **Defective Mismatch Repair Associated With MLH1**, **Defective Mismatch Repair Associated With PMS2**.

**Disease mechanism (Reactome):** PMS2 loss or alteration is curated in [Defective Mismatch Repair Associated With MLH1](https://reactome.org/content/detail/R-HSA-5545483), [Defective Mismatch Repair Associated With PMS2](https://reactome.org/content/detail/R-HSA-5632987).

### Pathways affected {#pathways}

PMS2 participates in **6 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective Mismatch Repair Associated With MLH1](https://reactome.org/content/detail/R-HSA-5545483) | curated |
| ⚕ [Defective Mismatch Repair Associated With PMS2](https://reactome.org/content/detail/R-HSA-5632987) | 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, single base insertion or deletion binding.

**Biological process:** meiotic mismatch repair, mismatch repair.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2024-12-18.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Uncertain Significance).

**Submission history:** 4 submissions (2020–2024); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-02 |
| Molecular Pathology, Peter Maccallum Cancer Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-12-18 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | criteria provided, single submitter | clinical testing | 2020-01-10 |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2024-05-14 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Lynch syndrome](https://sugi.bio/atlas/disease/lynch-syndrome/), [Lynch syndrome 4](https://sugi.bio/atlas/disease/lynch-syndrome-4/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Lynch syndrome, Lynch syndrome 4, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome, Colorectal cancer, hereditary nonpolyposis, type 4, Hereditary non-polyposis colorectal cancer, type 4.

## Same-residue context {#hotspot}

Residue **451** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [PMS2 p.Arg451fs](/variant/pms2-p-arg451fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related PMS2 variant pages (same residue, condition, or type): [PMS2 p.Arg451Gly](/variant/pms2-p-arg451gly), [PMS2 p.Arg451Thr](/variant/pms2-p-arg451thr), [PMS2 p.Arg451Lys](/variant/pms2-p-arg451lys), [PMS2 p.Arg451fs](/variant/pms2-p-arg451fs), [PMS2 p.Arg451Ser](/variant/pms2-p-arg451ser), [PMS2 c.1144+2T>A](/variant/pms2-c-1144-plus-2t-a), [PMS2 c.163+2T>C](/variant/pms2-c-163-plus-2t-c), [PMS2 c.164-2A>G](/variant/pms2-c-164-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 3387512). 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.*