Is PMS2 p.Ser248Ter (c.741_742insTGAAG) pathogenic?

PMS2 p.Ser248Ter (c.741742insTGAAG) is classified Likely pathogenic in PMS2 (ClinVar, Single submitter, 2 submitters; last evaluated 2018-01-26). No gnomAD frequency available for this variant; Associated with hereditary neoplastic syndrome.

What condition is associated with PMS2 p.Ser248Ter (c.741_742insTGAAG)?

PMS2 p.Ser248Ter (c.741_742insTGAAG) is associated with hereditary neoplastic syndrome, Lynch syndrome 4 (ClinVar).

How common is PMS2 p.Ser248Ter (c.741_742insTGAAG) in the general population?

PMS2 p.Ser248Ter (c.741_742insTGAAG) is no gnomAD frequency available for this variant (gnomAD).

PMS2 p.Ser248Ter

c.741_742insTGAAG · rs756653193 · VCV689355

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary neoplastic syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 7 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4.2	phastCons 1

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

dbSNP / gnomAD

No gnomAD frequency available for this variant. This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: PMS2
Protein: p.Ser248Ter
Coding: c.741_742insTGAAG
MANE Select: NM_000535
dbSNP: rs756653193
Type: Insertion
Location: chr7:5997387 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 248: an α-helix

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

Disease context

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

Also linked: Lynch syndrome 4

Similar variants

PMS2 p.Ser248fs Conflicting classifications of pathogenicity ★ ⚠ same residue
PMS2 p.Ser248Gly Uncertain significance ★★ ⚠ same residue
PMS2 p.Ser248= Benign/Likely benign ★★ same residue
PMS2 p.Ser248Thr Uncertain significance ★ ⚠ same residue
PMS2 p.Ser248delinsValTer Pathogenic ★ same residue
PMS2 p.Asp414Ter Pathogenic ★★ same condition
PMS2 p.Asp55delinsAsnTer Pathogenic/Likely pathogenic ★★ same condition
PMS2 p.Gly497fs Pathogenic/Likely 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-ser248ter (accessed [today's date]).

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