Is PALB2 p.Ala995fs (c.2982dup) pathogenic?

PALB2 p.Ala995fs (c.2982dup) is classified Pathogenic/Likely pathogenic in PALB2 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-05-07). Very rare (popmax 0.000254%, nfe); Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.Ala995fs (c.2982dup)?

PALB2 p.Ala995fs (c.2982dup) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome, breast-ovarian cancer, familial, susceptibility to, 5 (ClinVar).

How common is PALB2 p.Ala995fs (c.2982dup) in the general population?

PALB2 p.Ala995fs (c.2982dup) is very rare (popmax 0.000254%, nfe) (gnomAD).

How is Hereditary breast cancer inherited?

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

PALB2 p.Ala995fs

c.2982dup · rs180177127 · VCV126697

Pathogenic/Likely pathogenic Multiple submitters

Classification

Pathogenic/Likely pathogenic

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

Consequence

frameshift

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Conditions

hereditary breast carcinoma

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 9 of 13
Splicing
SpliceAI	—	not assessed · substitutions only
Constraint at this position
Conservation	phyloP 0.81	GERP -0.44, phastCons 0.82

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) · 3/1,180,016 alleles

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

Overall 0.000205% 3/1,461,862 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.Ala995fs
Coding: c.2982dup
MANE Select: NM_024675
dbSNP: rs180177127
Type: Duplication
Location: chr16:23622982 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 995: 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)

Full PALB2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

hereditary breast carcinoma — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: hereditary neoplastic syndrome breast-ovarian cancer, familial, susceptibility to, 5

For Hereditary breast cancer (Orphanet):

Inheritance: Autosomal dominant, Multigenic/multifactorial
Onset: Adult, Elderly

Similar variants

PALB2 p.Ala995Ser Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala995Val Uncertain significance ★★ ⚠ same residue
PALB2 p.Ala995= Benign/Likely benign ★★ same residue
PALB2 p.Ala995Gly Uncertain significance ★ ⚠ same residue
PALB2 p.Ala995Thr Uncertain significance ★ ⚠ same residue
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-ala995fs (accessed [today's date]).

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