Is PALB2 p.Pro5fs (c.12dup) pathogenic?

PALB2 p.Pro5fs (c.12dup) is classified Pathogenic in PALB2 (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-08-31). Very rare (popmax 0.0022%, sas); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Pro5fs (c.12dup)?

PALB2 p.Pro5fs (c.12dup) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Pro5fs (c.12dup) in the general population?

PALB2 p.Pro5fs (c.12dup) is very rare (popmax 0.0022%, sas) (gnomAD).

PALB2 p.Pro5fs

c.12dup · rs879254062 · VCV246045

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Conditions

hereditary neoplastic 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 1 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -1.4	GERP -3.4
Overall
CADD	23.6	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0022% South Asian · 2/90,968 alleles

Filtering AF 0.000365% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000137%

Overall 0.000186% 3/1,613,160 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,484
Remaining individualsnot grpmax-eligible	0.0016%	62,384

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: PALB2
Protein: p.Pro5fs
Coding: c.12dup
MANE Select: NM_024675
dbSNP: rs879254062
Type: Duplication
Location: chr16:23641145 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 5: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' region; the 'dna-binding (with the preference d loop > dsdna > ssdna)' region; the 'interaction with brca1' region

Full PALB2 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: hereditary breast ovarian cancer syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Pro5Leu Uncertain significance ★★ ⚠ same residue
PALB2 p.Pro5= Benign/Likely benign ★★ same residue
PALB2 p.Pro5Ala Uncertain significance ★ ⚠ same residue
PALB2 p.Pro5Ser Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Ala995fs Pathogenic/Likely pathogenic ★★ same condition
PALB2 p.Arg153fs Pathogenic ★★ same condition
PALB2 p.Arg464fs Pathogenic ★★ same condition
PALB2 p.Asn280fs 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/palb2-p-pro5fs (accessed [today's date]).

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