Is PMS2 p.Lys706fs (c.2117del) pathogenic?

PMS2 p.Lys706fs (c.2117del) is classified Pathogenic in PMS2 (ClinVar, Multiple submitters, 20 submitters; last evaluated 2026-01-26). Very rare (popmax 0.00102%, nfe); Associated with hereditary nonpolyposis colon cancer.

What condition is associated with PMS2 p.Lys706fs (c.2117del)?

PMS2 p.Lys706fs (c.2117del) is associated with hereditary nonpolyposis colon cancer, endometrial carcinoma, Lynch syndrome (ClinVar).

How common is PMS2 p.Lys706fs (c.2117del) in the general population?

PMS2 p.Lys706fs (c.2117del) is very rare (popmax 0.00102%, nfe) (gnomAD).

PMS2 p.Lys706fs

c.2117del · rs587782704 · VCV142765

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 20 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00102%, nfe)

Conditions

hereditary nonpolyposis colon cancer

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 12 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.5
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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00102% European (non-Finnish) · 12/1,176,464 alleles

Filtering AF 0.000544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00043%

Overall 0.000825% 12/1,454,606 alleles · very rare

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Cancer therapy — CIViC

Disease	Therapies	Level	Significance
Glioblastoma	Nivolumab	C	Sensitivity/Response

Variant & gene context

Gene: PMS2
Protein: p.Lys706fs
Coding: c.2117del
MANE Select: NM_000535
dbSNP: rs587782704
Type: Deletion
Location: chr7:5982881 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB

Full PMS2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary nonpolyposis colon cancer — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: endometrial carcinoma Lynch syndrome Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Lys706Asn Uncertain significance ★★ ⚠ same residue
PMS2 p.Lys706= Benign/Likely benign ★★ same residue
PMS2 p.Lys706Arg Uncertain significance ★ same residue
PMS2 p.Lys706Glu Uncertain significance ★ ⚠ same residue
PMS2 p.Lys706_Glu710del Uncertain significance ★ same residue
PMS2 c.1145-1350_*20545del Pathogenic ★★★ same condition
PMS2 c.1145-?_2174+?del Pathogenic ★★★ same condition
PMS2 c.2276-113_2445+1596del 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-lys706fs (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown