Is PMS2 p.Val816fs (c.2444_2445insTT) pathogenic?

PMS2 p.Val816fs (c.24442445insTT) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2024-02-16). Absent from gnomAD; Associated with Lynch syndrome 4.

What condition is associated with PMS2 p.Val816fs (c.2444_2445insTT)?

PMS2 p.Val816fs (c.2444_2445insTT) is associated with Lynch syndrome 4, hereditary neoplastic syndrome, hereditary nonpolyposis colon cancer (ClinVar).

How common is PMS2 p.Val816fs (c.2444_2445insTT) in the general population?

PMS2 p.Val816fs (c.2444_2445insTT) is absent from gnomAD (gnomAD).

How is Lynch syndrome inherited?

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

PMS2 p.Val816fs

c.2444_2445insTT · rs2128671557 · VCV1192211

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

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	escapes	premature termination codon within the last 50 nt of the penultimate exon (14 of 15, 0 nt from its 3' end) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.005	phastCons 0.032
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

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.Val816fs
Coding: c.2444_2445insTT
MANE Select: NM_000535
dbSNP: rs2128671557
Type: Insertion
Location: chr7:5977588 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 816: a UniProt-annotated variant site (in lynch4; uncertain significance; may affect protein stability; no effect on dna mismatch repair activity in an in vitro assay, compared to wild-type)

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

Disease context

Lynch syndrome 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome hereditary nonpolyposis colon cancer

For Lynch syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult

Similar variants

PMS2 p.Val816Glu Uncertain significance ★★ ⚠ same residue
PMS2 p.Val816Leu Uncertain significance ★★ ⚠ same residue
PMS2 p.Val816Met Uncertain significance ★★ ⚠ same residue
PMS2 p.Val816= Likely benign ★★ same residue
PMS2 p.Asp414Ter Pathogenic ★★ same condition
PMS2 p.Asp55delinsAsnTer Pathogenic/Likely pathogenic ★★ same condition
PMS2 p.Gly497fs Pathogenic/Likely pathogenic ★★ same condition
PMS2 p.Gly72fs 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-val816fs (accessed [today's date]).

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