PMS2 p.Ser46fs
c.136_139del · VCV3308116
Pathogenic
Multiple submitters
Classification
Pathogenic
ClinVar
Review
Multiple submitters ★★☆☆
ClinVar · 2 submitters
Consequence
frameshift
predicted LoF
gnomAD v4.1
Rare
Conditions
2
Lynch syndrome 4
Computational evidence
| Protein change | ||
| Missense predictors do not apply to this variant type; conservation carries the signal. | ||
| Consequence | frameshift | predicted loss-of-function in a haploinsufficient gene (ClinGen) |
|---|---|---|
| NMD | predicted | premature termination codon in exon 2 of 15 |
| Splicing | ||
| SpliceAI | — | not assessed · substitutions only |
| Constraint at this position | ||
| Conservation | phyloP 11 | phastCons 1 |
| Region caveats | ||
| Repeat context | seg dup | · reads may not map uniquely · confidence, not pathogenicity |
Predicted loss-of-function is descriptive, not an applied PVS1 code.
Variant & gene context
- Gene
- PMS2
- Protein
- p.Ser46fs
- Coding
- c.136_139del
- MANE Select
- NM_000535
- Type
- Deletion
- Location
- chr7:6005916 (GRCh38)
- Gene constraint
- LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
- Structure
- AlphaFold pLDDT 71.37 · 9 PDB
- Residue 46
- a UniProt-annotated variant site (in mmrcs4 and lynch4; strongly decreased dna mismatch repair activity; no effect on protein abundance; no effect on subcellular localization); a UniProt-annotated variant site (in lynch4; strongly decreased dna mismatch repair activity); an α-helix
Disease context
Lynch syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatmentsAlso linked: hereditary neoplastic syndrome
For Lynch syndrome (Orphanet):
- Inheritance
- Autosomal dominant
- Onset
- Adult
Similar variants
- PMS2 p.Ser46Ile Likely pathogenic ★★★ same residue
- PMS2 p.Ser46Asn Pathogenic/Likely pathogenic ★★ same residue
- PMS2 p.Ser46Arg Uncertain significance ★ ⚠ same residue
- PMS2 p.Ser46= Likely benign ★ same residue
- PMS2 c.989-296_1144+706del Pathogenic ★★★ same condition
- PMS2 p.Glu180_Tyr181insTer Pathogenic ★★★ same condition
- PMS2 p.Leu731fs Pathogenic ★★★ same condition
- PMS2 p.Phe788fs Pathogenic ★★★ same condition
Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →
Cite Sugi Variant
Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/pms2-p-ser46fs (accessed [today's date]).
Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown