Is PMS2 p.Phe506fs (c.1515del) pathogenic?

PMS2 p.Phe506fs (c.1515del) is classified Pathogenic in PMS2 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2020-12-30). Very rare (popmax 0.00223%, eas); Associated with Hereditary nonpolyposis colorectal neoplasms.

What condition is associated with PMS2 p.Phe506fs (c.1515del)?

PMS2 p.Phe506fs (c.1515del) is associated with Hereditary nonpolyposis colorectal neoplasms, hereditary neoplastic syndrome, hereditary nonpolyposis colon cancer (ClinVar).

How common is PMS2 p.Phe506fs (c.1515del) in the general population?

PMS2 p.Phe506fs (c.1515del) is very rare (popmax 0.00223%, eas) (gnomAD).

PMS2 p.Phe506fs

c.1515del · rs1583319050 · VCV819374

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 -2.6
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 0.00223% East Asian · 1/44,872 alleles

Overall 6.84e-05% 1/1,461,856 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.

Variant & gene context

Gene: PMS2
Protein: p.Phe506fs
Coding: c.1515del
MANE Select: NM_000535
dbSNP: rs1583319050
Type: Deletion
Location: chr7:5987250 (GRCh38)
Gene constraint: LOEUF 0.898 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 71.37 · 9 PDB
Residue 506: the 'disordered' region

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: hereditary neoplastic syndrome hereditary nonpolyposis colon cancer

Similar variants

PMS2 p.Phe506Cys Uncertain significance ★★ ⚠ same residue
PMS2 p.Phe506= Benign/Likely benign ★★ same residue
PMS2 p.Phe506Tyr Uncertain significance ★ ⚠ same residue
PMS2 c.989-296_1144+706del Pathogenic ★★★ same condition
PMS2 p.Glu180_Tyr181insTer Pathogenic ★★★ same condition
PMS2 p.Leu731fs Pathogenic ★★★ same condition
PMS2 p.Phe788fs Pathogenic ★★★ same condition
PMS2 c.1144+1del 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-phe506fs (accessed [today's date]).

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