Is PMS2 p.Ser22fs (c.63_75del) pathogenic?

PMS2 p.Ser22fs (c.6375del) is classified Likely pathogenic in PMS2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-05-08). Very rare (popmax 0.00136%, nfe); Associated with Lynch syndrome.

What condition is associated with PMS2 p.Ser22fs (c.63_75del)?

PMS2 p.Ser22fs (c.63_75del) is associated with Lynch syndrome (ClinVar).

How common is PMS2 p.Ser22fs (c.63_75del) in the general population?

PMS2 p.Ser22fs (c.63_75del) is very rare (popmax 0.00136%, nfe) (gnomAD).

How is Lynch syndrome inherited?

Typically Autosomal dominant (Orphanet). A genetic counselor can assess individual risk for a family.

PMS2 p.Ser22fs

c.63_75del · rs2536589369 · VCV3075776

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00136%, nfe)

Conditions

Lynch syndrome

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 6.2	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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00136% European (non-Finnish) · 16/1,179,818 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00106% 17/1,610,768 alleles · very rare exomes 17/1,458,544 · genomes 0/152,224 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00161%	62,304
European (non-Finnish)grpmax	0.00136%	73,739

Remaining individuals shows a higher raw frequency than the grpmax group above it. 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.

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.

Variant & gene context

Gene: PMS2
Protein: p.Ser22fs
Coding: c.63_75del
MANE Select: NM_000535
dbSNP: rs2536589369
Type: Deletion
Location: chr7:6005980 (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

Lynch syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

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
PMS2 c.2276-91_2445+790del Pathogenic ★★★ same condition
PMS2 c.24-?_163+?del Pathogenic ★★★ same condition
PMS2 c.354-?_803+?del Pathogenic ★★★ same condition
PMS2 c.354-?_(*160_? Pathogenic ★★★ same condition
PMS2 c.538-478_705+456del 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-ser22fs (accessed [today's date]).

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