Is PALB2 p.Phe1016fs (c.3048del) pathogenic?

PALB2 p.Phe1016fs (c.3048del) is classified Pathogenic/Likely pathogenic in PALB2 (ClinVar, Multiple submitters, 15 submitters; last evaluated 2025-12-10). Very rare (popmax 0.000169%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Phe1016fs (c.3048del)?

PALB2 p.Phe1016fs (c.3048del) is associated with hereditary neoplastic syndrome, hereditary breast ovarian cancer syndrome, Fanconi anemia complementation group N (ClinVar).

How common is PALB2 p.Phe1016fs (c.3048del) in the general population?

PALB2 p.Phe1016fs (c.3048del) is very rare (popmax 0.000169%, nfe) (gnomAD).

PALB2 p.Phe1016fs

c.3048del · rs515726104 · VCV126707

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 15 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

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 10 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 4	GERP 1.9, phastCons 1

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,996 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000124% 2/1,614,106 alleles · very rare exomes 2/1,461,822 · genomes 0/152,284 · 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: PALB2
Protein: p.Phe1016fs
Coding: c.3048del
MANE Select: NM_024675
dbSNP: rs515726104
Type: Deletion
Location: chr16:23621427 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 1016: the 'required for interaction with polh and polh dna synthesis stimulation' region; the 'interaction with rad51, brca2 and polh' region; a UniProt-annotated variant site (risk factor for brovca5); a UniProt-annotated variant site (in fancn; risk factor for brovca5); a β-strand

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 Fanconi anemia complementation group N pancreatic cancer, susceptibility to, 3 hereditary breast carcinoma

Similar variants

PALB2 p.Phe1016Cys Uncertain significance ★★ ⚠ same residue
PALB2 p.Phe1016Leu Uncertain significance ★★ ⚠ same residue
PALB2 p.Phe1016Ser Uncertain significance ★★ ⚠ same residue
PALB2 p.Phe1016= Likely benign ★ same residue
PALB2 p.Glu178fs Pathogenic ★★★ same condition
PALB2 p.Gly1121fs Likely pathogenic ★★★ same condition
PALB2 p.Leu531fs Pathogenic ★★★ same condition
PALB2 p.Ser172fs 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-phe1016fs (accessed [today's date]).

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