Is PMS2 p.Phe620fs (c.1859_1860insAT) pathogenic?

PMS2 p.Phe620fs (c.18591860insAT) is classified Pathogenic/Likely pathogenic in PMS2 (ClinVar, Multiple submitters, 7 submitters; last evaluated 2025-10-18). Very rare (popmax 8.47e-05%, nfe); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Phe620fs (c.1859_1860insAT)?

PMS2 p.Phe620fs (c.1859_1860insAT) is associated with Hereditary nonpolyposis colorectal neoplasms, Lynch syndrome 4, hereditary neoplastic syndrome (ClinVar).

How common is PMS2 p.Phe620fs (c.1859_1860insAT) in the general population?

PMS2 p.Phe620fs (c.1859_1860insAT) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

PMS2 p.Phe620fs

c.1859_1860insAT · rs756358866 · VCV1458544

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 7 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Conditions

Hereditary nonpolyposis colorectal neoplasms

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 11 of 15
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.63	phastCons 0.94
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 8.47e-05% European (non-Finnish) · 1/1,180,034 alleles

Overall 6.2e-05% 1/1,614,178 alleles · very rare exomes 1/1,461,882 · genomes 0/152,296 · joint denominator

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.Phe620fs
Coding: c.1859_1860insAT
MANE Select: NM_000535
dbSNP: rs756358866
Type: Insertion
Location: chr7:5986905 (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 colorectal neoplasms — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Lynch syndrome 4 hereditary neoplastic syndrome

Similar variants

PMS2 p.Phe620= Benign/Likely benign ★★ same residue
PMS2 p.Phe620Ile Uncertain significance ★ same residue
PMS2 p.Phe620Ser Uncertain significance ★ ⚠ same residue
PMS2 p.Phe620Tyr Uncertain significance ★ same residue
PMS2 p.Phe620Val Uncertain significance ★ 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-phe620fs (accessed [today's date]).

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