Is PALB2 p.Ser259Ter (c.774dup) pathogenic?

PALB2 p.Ser259Ter (c.774dup) is classified Pathogenic in PALB2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-08). Absent from gnomAD; Associated with hereditary breast ovarian cancer syndrome.

What condition is associated with PALB2 p.Ser259Ter (c.774dup)?

PALB2 p.Ser259Ter (c.774dup) is associated with hereditary breast ovarian cancer syndrome (ClinVar).

How common is PALB2 p.Ser259Ter (c.774dup) in the general population?

PALB2 p.Ser259Ter (c.774dup) is absent from gnomAD (gnomAD).

How is Hereditary breast and/or ovarian cancer syndrome inherited?

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

PALB2 p.Ser259Ter

c.774dup · rs2506500182 · VCV2506056

Pathogenic Single submitter

Classification

Pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Not reported

no gnomAD frequency available for this variant

Conditions

hereditary breast ovarian cancer syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function in a haploinsufficient gene (ClinGen)
NMD	predicted	premature termination codon in exon 4 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -4.7	GERP -3.6

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: PALB2
Protein: p.Ser259Ter
Coding: c.774dup
MANE Select: NM_024675
dbSNP: rs2506500182
Type: Duplication
Location: chr16:23635771 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 259: the 'disordered' 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 breast ovarian cancer syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Hereditary breast and/or ovarian cancer syndrome (Orphanet):

Inheritance: Autosomal dominant
Onset: Adult, Elderly

Similar variants

PALB2 p.Lys268fs Pathogenic/Likely pathogenic ★★ same condition
PALB2 p.Pro1153fs Pathogenic ★★ same condition
PALB2 p.Pro5fs Pathogenic ★★ same condition
PALB2 p.Ser254fs Pathogenic/Likely pathogenic ★★ same condition
PALB2 p.Ser259Asn Uncertain significance ★★ ⚠ same residue
PALB2 p.Ser259fs Likely pathogenic ★ same residue
PALB2 p.Ser259Arg Uncertain significance ★ ⚠ same residue
PALB2 p.Ser259Gly Uncertain significance ★ ⚠ same residue

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-ser259ter (accessed [today's date]).

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