# NM_000535.7(PMS2):c.2252T>C (p.Phe751Ser)

https://sugi.bio/variant/pms2-p-phe751ser

## Summary

**PMS2 p.Phe751Ser (c.2252T>C)** is classified **Uncertain significance** in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-24). AlphaMissense: likely pathogenic (0.9981); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Single submitter · 1 submitter · 1 linked condition · AlphaMissense likely pathogenic · 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 1 submitter, 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.Phe751Ser |
| Coding change (HGVS c.) | c.2252T>C |
| MANE Select transcript | [NM_000535](https://www.ncbi.nlm.nih.gov/nuccore/NM_000535) |
| Variant type | single nucleotide variant |
| Location | chr7:5978619-5978619 (GRCh38) |
| ClinVar | [VCV4756213](https://www.ncbi.nlm.nih.gov/clinvar/variation/4756213/) |

**All HGVS expressions:** `LRG_161:g.35488T>C`, `LRG_161t1:c.2252T>C`, `NC_000007.13:g.6018250A>G`, `NC_000007.14:g.5978619A>G`, `NG_008466.1:g.35488T>C`, `NM_000535.7:c.2252T>C`, `NM_001322003.2:c.1847T>C`, `NM_001322004.2:c.1847T>C`, `NM_001322005.2:c.1847T>C`, `NM_001322006.2:c.2096T>C`, `NM_001322007.2:c.1934T>C`, `NM_001322008.2:c.1934T>C`, `NM_001322009.2:c.1847T>C`, `NM_001322010.2:c.1691T>C`, `NM_001322011.2:c.1319T>C`, `NM_001322012.2:c.1319T>C`, `NM_001322013.2:c.1679T>C`, `NM_001322014.2:c.2252T>C`, `NM_001322015.2:c.1943T>C`, `NM_001406866.1:c.2438T>C`, `NM_001406868.1:c.2276T>C`, `NM_001406869.1:c.2144T>C`, `NM_001406870.1:c.2096T>C`, `NM_001406871.1:c.2175-905T>C`, `NM_001406872.1:c.2084T>C`, `NM_001406873.1:c.2054T>C`, `NM_001406874.1:c.2084T>C`, `NM_001406875.1:c.1943T>C`, `NM_001406876.1:c.1934T>C`, `NM_001406877.1:c.1943T>C`, `NM_001406878.1:c.1943T>C`, `NM_001406879.1:c.1943T>C`, `NM_001406880.1:c.1943T>C`, `NM_001406881.1:c.1943T>C`, `NM_001406882.1:c.1943T>C`, `NM_001406883.1:c.1934T>C`, `NM_001406884.1:c.1928T>C`, `NM_001406885.1:c.1916T>C`, `NM_001406886.1:c.1886T>C`, `NM_001406887.1:c.1847T>C`, `NM_001406888.1:c.1847T>C`, `NM_001406889.1:c.1847T>C`, `NM_001406890.1:c.1847T>C`, `NM_001406891.1:c.1847T>C`, `NM_001406892.1:c.1847T>C`, `NM_001406893.1:c.1847T>C`, `NM_001406894.1:c.1847T>C`, `NM_001406895.1:c.1847T>C`, `NM_001406896.1:c.1847T>C`, `NM_001406897.1:c.1847T>C`, `NM_001406898.1:c.1847T>C`, `NM_001406899.1:c.1847T>C`, `NM_001406900.1:c.1787T>C`, `NM_001406901.1:c.1778T>C`, `NM_001406902.1:c.1778T>C`, `NM_001406903.1:c.1766T>C`, `NM_001406904.1:c.1739T>C`, `NM_001406905.1:c.1739T>C`, `NM_001406906.1:c.1691T>C`, `NM_001406907.1:c.1691T>C`, `NM_001406908.1:c.1679T>C`, `NM_001406909.1:c.1679T>C`, `NM_001406910.1:c.1602-905T>C`, `NM_001406911.1:c.1481T>C`, `NM_001406912.1:c.1049T>C`, `NR_136154.1:n.2339T>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.9981)
- REVEL 0.945 (strongly pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -16.191 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 11.113, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in PMS2 (of 5,081 modeled).
- CADD: **PHRED 29.9**. 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.*
- Regional missense constraint: **o/e 0.40** across the covering region of the MANE Select transcript (5,973,402–5,986,797), spanning 13,395 bp. Chi-square p 2e-20. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- 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}


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. 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 Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-24.

**Submitter consensus:** unanimous (1/1 Uncertain significance).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-08-24 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Tumor predisposition, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome.

## Similar variants {#similar}

Related PMS2 variant pages (same residue, condition, or type): [PMS2 p.Phe751=](/variant/pms2-p-phe751), [PMS2 p.Phe751Leu](/variant/pms2-p-phe751leu), [PMS2 p.Phe751Ile](/variant/pms2-p-phe751ile), [PMS2 c.163+2T>C](/variant/pms2-c-163-plus-2t-c), [PMS2 c.164-2A>G](/variant/pms2-c-164-minus-2a-g), [PMS2 c.2007-1G>A](/variant/pms2-c-2007-minus-1g-a), [PMS2 c.2174+1G>A](/variant/pms2-c-2174-plus-1g-a), [PMS2 c.705+1G>T](/variant/pms2-c-705-plus-1g-t).

### 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 4756213). 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.*