# NM_000535.7(PMS2):c.1245_1246del (p.Ser416fs)

https://sugi.bio/variant/pms2-p-ser416fs

## Summary

**PMS2 p.Ser416fs (c.1245_1246del)** is classified **Pathogenic** in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-02-28). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2535827000 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the PMS2 gene that is reported as disease-causing, but on limited review, 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.Ser416fs |
| Coding change (HGVS c.) | c.1245_1246del |
| MANE Select transcript | [NM_000535](https://www.ncbi.nlm.nih.gov/nuccore/NM_000535) |
| dbSNP | [rs2535827000](https://www.ncbi.nlm.nih.gov/snp/rs2535827000/) |
| Variant type | Microsatellite |
| Location | chr7:5987519-5987520 (GRCh38) |
| ClinVar | [VCV1759171](https://www.ncbi.nlm.nih.gov/clinvar/variation/1759171/) |

**All HGVS expressions:** `LRG_161:g.26585GT[1]`, `LRG_161t1:c.1243_1244GT[1]`, `NC_000007.13:g.6027150AC[1]`, `NC_000007.14:g.5987519AC[1]`, `NG_008466.1:g.26585GT[1]`, `NM_000535.5:c.1243_1244GT[1]`, `NM_000535.5:c.1245_1246delGT`, `NM_000535.7:c.1245_1246del`, `NM_001018040.1:c.838_839GT[1]`, `NM_001322003.2:c.840_841del`, `NM_001322004.2:c.840_841del`, `NM_001322005.2:c.840_841del`, `NM_001322006.2:c.1089_1090del`, `NM_001322007.2:c.927_928del`, `NM_001322008.2:c.927_928del`, `NM_001322009.2:c.840_841del`, `NM_001322010.2:c.684_685del`, `NM_001322011.2:c.312_313del`, `NM_001322012.2:c.312_313del`, `NM_001322013.2:c.672_673del`, `NM_001322014.2:c.1245_1246del`, `NM_001322015.2:c.936_937del`, `NM_001406866.1:c.1429_1430GT[1]`, `NM_001406868.1:c.1267_1268GT[1]`, `NM_001406869.1:c.1135_1136GT[1]`, `NM_001406870.1:c.1087_1088GT[1]`, `NM_001406871.1:c.1243_1244GT[1]`, `NM_001406872.1:c.1243_1244GT[1]`, `NM_001406873.1:c.1045_1046GT[1]`, `NM_001406874.1:c.1075_1076GT[1]`, `NM_001406875.1:c.934_935GT[1]`, `NM_001406876.1:c.925_926GT[1]`, `NM_001406877.1:c.934_935GT[1]`, `NM_001406878.1:c.934_935GT[1]`, `NM_001406879.1:c.934_935GT[1]`, `NM_001406880.1:c.934_935GT[1]`, `NM_001406881.1:c.934_935GT[1]`, `NM_001406882.1:c.934_935GT[1]`, `NM_001406883.1:c.925_926GT[1]`, `NM_001406884.1:c.919_920GT[1]`, `NM_001406885.1:c.907_908GT[1]`, `NM_001406886.1:c.877_878GT[1]`, `NM_001406887.1:c.838_839GT[1]`, `NM_001406888.1:c.838_839GT[1]`, `NM_001406889.1:c.838_839GT[1]`, `NM_001406890.1:c.838_839GT[1]`, `NM_001406891.1:c.838_839GT[1]`, `NM_001406892.1:c.838_839GT[1]`, `NM_001406893.1:c.838_839GT[1]`, `NM_001406894.1:c.838_839GT[1]`, `NM_001406895.1:c.838_839GT[1]`, `NM_001406896.1:c.838_839GT[1]`, `NM_001406897.1:c.838_839GT[1]`, `NM_001406898.1:c.838_839GT[1]`, `NM_001406899.1:c.838_839GT[1]`, `NM_001406900.1:c.778_779GT[1]`, `NM_001406901.1:c.769_770GT[1]`, `NM_001406902.1:c.769_770GT[1]`, `NM_001406903.1:c.925_926GT[1]`, `NM_001406904.1:c.730_731GT[1]`, `NM_001406905.1:c.730_731GT[1]`, `NM_001406906.1:c.682_683GT[1]`, `NM_001406907.1:c.682_683GT[1]`, `NM_001406908.1:c.838_839GT[1]`, `NM_001406909.1:c.670_671GT[1]`, `NM_001406910.1:c.838_839GT[1]`, `NM_001406911.1:c.472_473GT[1]`, `NR_003085.2:n.1325_1326GT[1]`, `NR_136154.1:n.1330GT[1]`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 3.838, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 11 of 15**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no microsatellite variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Repeat context: **segmental_duplication** (chr7:6735644). Short reads may not map uniquely here, so both the call and its population frequency are less reliable. *A qualifier on how reliably this variant can be called and counted — not a pathogenicity signal.*
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **416** 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.Ser416fs 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2019-02-28.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2019-02-28 |

## Associated conditions {#conditions}

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

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

## Similar variants {#similar}

Related PMS2 variant pages (same residue, condition, or type): [PMS2 p.Ser416Cys](/variant/pms2-p-ser416cys), [PMS2 p.Ser416Phe](/variant/pms2-p-ser416phe), [PMS2 p.Ser416=](/variant/pms2-p-ser416), [PMS2 p.Lys748fs](/variant/pms2-p-lys748fs), [PMS2 p.Ala116fs](/variant/pms2-p-ala116fs), [PMS2 p.Asp286fs](/variant/pms2-p-asp286fs), [PMS2 p.Cys252_Glu253delinsTer](/variant/pms2-p-cys252-glu253delinster), [PMS2 p.Gln374fs](/variant/pms2-p-gln374fs).

### 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 1759171). 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.*