Is PALB2 p.Ser299fs (c.896_897del) pathogenic?

PALB2 p.Ser299fs (c.896897del) is classified Pathogenic in PALB2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-11-18). Very rare (popmax 0.000254%, nfe); Associated with hereditary neoplastic syndrome.

What condition is associated with PALB2 p.Ser299fs (c.896_897del)?

PALB2 p.Ser299fs (c.896_897del) is associated with hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Ser299fs (c.896_897del) in the general population?

PALB2 p.Ser299fs (c.896_897del) is very rare (popmax 0.000254%, nfe) (gnomAD).

PALB2 p.Ser299fs

c.896_897del · rs1967011347 · VCV921123

Pathogenic Multiple submitters

Classification

Pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, 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 4 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP -0.24	GERP -3.4

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000254% European (non-Finnish) · 3/1,179,960 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000205% 3/1,461,778 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: PALB2
Protein: p.Ser299fs
Coding: c.896_897del
MANE Select: NM_024675
dbSNP: rs1967011347
Type: Microsatellite
Location: chr16:23635649 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 299: 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 carcinoma

Similar variants

PALB2 p.Ser299Phe Uncertain significance ★★ ⚠ same residue
PALB2 p.Ser299= Conflicting classifications of pathogenicity ★ same residue
PALB2 p.Ser299Thr Uncertain significance ★ ⚠ same residue
PALB2 p.Asn930fs Pathogenic ★★★ same condition
PALB2 p.Arg975fs Pathogenic ★★ same condition
PALB2 p.Asp161fs Pathogenic ★★ same condition
PALB2 p.Cys768fs Pathogenic ★★ same condition
PALB2 p.Cys802_Asp803delinsTer 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-ser299fs (accessed [today's date]).

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