# NM_000535.7(PMS2):c.2253T>C (p.Phe751=)

https://sugi.bio/variant/pms2-p-phe751

## Summary

**PMS2 p.Phe751= (c.2253T>C)** is classified **Benign** in PMS2 (ClinVar, Expert panel, 23 submitters; last evaluated 2013-09-05). Ultra-rare (popmax 0.042%, afr); Associated with Lynch syndrome.

**At a glance:** Benign · review: Expert panel · rsID rs1805325 · 23 submitters · 5 linked conditions · ultra-rare (popmax 0.042%, afr)

## For patients & families {#patients}

This is a change in the PMS2 gene that is classified as benign — not considered disease-causing, submitted by 23 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 | PMS2 is a diagnostic-grade gene on 23 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 | [PMS2](https://sugi.bio/atlas/gene/PMS2/) |
| Protein change (HGVS p.) | p.Phe751= |
| Coding change (HGVS c.) | c.2253T>C |
| MANE Select transcript | [NM_000535](https://www.ncbi.nlm.nih.gov/nuccore/NM_000535) |
| dbSNP | [rs1805325](https://www.ncbi.nlm.nih.gov/snp/rs1805325/) |
| Variant type | single nucleotide variant |
| Location | chr7:5978618-5978618 (GRCh38) |
| ClinVar | [VCV36688](https://www.ncbi.nlm.nih.gov/clinvar/variation/36688/) |

**All HGVS expressions:** `LRG_161:g.35489T>C`, `LRG_161t1:c.2253T>C`, `NC_000007.13:g.6018249A>G`, `NC_000007.14:g.5978618A>G`, `NG_008466.1:g.35489T>C`, `NM_000535.7:c.2253T>C`, `NM_001322003.2:c.1848T>C`, `NM_001322004.2:c.1848T>C`, `NM_001322005.2:c.1848T>C`, `NM_001322006.2:c.2097T>C`, `NM_001322007.2:c.1935T>C`, `NM_001322008.2:c.1935T>C`, `NM_001322009.2:c.1848T>C`, `NM_001322010.2:c.1692T>C`, `NM_001322011.2:c.1320T>C`, `NM_001322012.2:c.1320T>C`, `NM_001322013.2:c.1680T>C`, `NM_001322014.2:c.2253T>C`, `NM_001322015.2:c.1944T>C`, `NR_136154.1:n.2340T>C`

## 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 2.622, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 9.286**. 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: **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 (gnomAD v4.1): grpmax **0.042%** (afr) · FAF95 0.0304% · FAF99 0.0264% · 31/73,852 in the highest group · 595/1,603,588 alleles overall — ultra-rare (popmax 0.042%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 1.32% | 76 |
| Remaining individuals (not grpmax-eligible) | 0.0887% | 1,128 |
| African / African-American (grpmax) | 0.042% | 2,382 |
| East Asian | 0.0157% | 6,354 |
| European (non-Finnish) | 0.00878% | 11,392 |
| Finnish (not grpmax-eligible) | 0.00791% | 12,648 |
| South Asian | 0.00662% | 15,102 |
| Admixed American | 0.00502% | 19,937 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2013-09-05.

**Submitter consensus:** conflicting (20 Benign, 2 Likely benign, 1 Uncertain significance).

**Submission history:** 23 submissions (2011–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Pathway Genomics | Benign | no assertion criteria provided | clinical testing | 2014-07-24 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2021-07-26 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing |  |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing | 2016-11-10 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Benign | no assertion criteria provided | clinical testing |  |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | no assertion criteria provided | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Benign | criteria provided, single submitter | clinical testing | 2021-09-29 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2018-12-06 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2023-04-05 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2011-08-18 |
| International Society for Gastrointestinal Hereditary Tumours (InSiGHT) | Benign | reviewed by expert panel | research | 2013-09-05 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-04-01 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-18 |
| Illumina Laboratory Services, Illumina | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-04-27 |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2020-10-13 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-09-15 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2018-03-16 |
| Counsyl | Benign | no assertion criteria provided | clinical testing | 2016-06-01 |

## Associated conditions {#conditions}

[Lynch syndrome](https://sugi.bio/atlas/disease/lynch-syndrome/), [endometrial carcinoma](https://sugi.bio/atlas/disease/endometrial-carcinoma/), [Lynch syndrome 1](https://sugi.bio/atlas/disease/lynch-syndrome-1/), [Lynch syndrome 4](https://sugi.bio/atlas/disease/lynch-syndrome-4/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Lynch syndrome, Lynch syndrome 1, Hereditary cancer-predisposing syndrome, not specified, Lynch syndrome 4, Hereditary nonpolyposis colorectal neoplasms, Endometrial carcinoma, not provided, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome.

## Similar variants {#similar}

Related PMS2 variant pages (same residue, condition, or type): [PMS2 p.Phe751Leu](/variant/pms2-p-phe751leu), [PMS2 p.Phe751Ile](/variant/pms2-p-phe751ile), [PMS2 p.Phe751Ser](/variant/pms2-p-phe751ser), [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), [PMS2 c.2007-1G>A](/variant/pms2-c-2007-minus-1g-a), [PMS2 c.2174+1G>A](/variant/pms2-c-2174-plus-1g-a).

### 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 36688). 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.*