Is PALB2 p.His593= (c.1779T>C) pathogenic?

PALB2 p.His593= (c.1779T>C) is classified Conflicting classifications of pathogenicity in PALB2 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2025-01-14). Very rare (popmax 0.00133%, afr); Associated with hereditary breast carcinoma.

What condition is associated with PALB2 p.His593= (c.1779T>C)?

PALB2 p.His593= (c.1779T>C) is associated with hereditary breast carcinoma, hereditary neoplastic syndrome (ClinVar).

How common is PALB2 p.His593= (c.1779T>C) in the general population?

PALB2 p.His593= (c.1779T>C) is very rare (popmax 0.00133%, afr) (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.His593=

c.1779T>C · rs1475548158 · VCV652679

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Conditions

hereditary breast carcinoma

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -0.56
Overall
CADD	2.439	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00133% African / African-American · 1/75,058 alleles

Overall 6.84e-05% 1/1,461,776 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.His593=
Coding: c.1779T>C
MANE Select: NM_024675
dbSNP: rs1475548158
Type: single nucleotide variant
Location: chr16:23630375 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 593: 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

For Hereditary breast cancer (Orphanet):

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

Similar variants

PALB2 p.His593Arg Uncertain significance ★★ ⚠ same residue
PALB2 p.His593Asp Uncertain significance ★ ⚠ same residue
PALB2 p.His593Gln Uncertain significance ★ ⚠ same residue
PALB2 p.His593fs Pathogenic ★ same residue
PALB2 c.3350+4A>G Likely pathogenic ★★★ same condition
PALB2 p.Arg1117Lys Pathogenic ★★★ ⚠ same condition
PALB2 p.Gln228Ter Pathogenic ★★★ same condition
PALB2 p.Gln692Ter Likely 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-his593 (accessed [today's date]).

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