Is PALB2 p.Lys45= (c.135G>A) pathogenic?

PALB2 p.Lys45= (c.135G>A) is classified Likely benign in PALB2 (ClinVar, Expert panel, 5 submitters; last evaluated 2023-04-05). Very rare (popmax 0.000169%, nfe); Associated with PALB2-related cancer predisposition.

What condition is associated with PALB2 p.Lys45= (c.135G>A)?

PALB2 p.Lys45= (c.135G>A) is associated with PALB2-related cancer predisposition, hereditary neoplastic syndrome, hereditary breast carcinoma (ClinVar).

How common is PALB2 p.Lys45= (c.135G>A) in the general population?

PALB2 p.Lys45= (c.135G>A) is very rare (popmax 0.000169%, nfe) (gnomAD).

PALB2 p.Lys45=

c.135G>A · rs753270291 · VCV230997

Likely benign Expert panel

Classification

Likely benign

ClinVar

Review

Expert panel ★★★☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Conditions

PALB2-related cancer predisposition

ClinGen expert panel — Hereditary Breast, Ovarian and Pancreatic Cancer VCEP

Likely Benign for PALB2-related cancer predisposition. Applied ACMG criteria (verbatim):

BP7 BP4

Curation rationale (ClinGen, verbatim)

The c.135G>A (p.Lys45=) variant is a synonymous (silent) variant that is not predicted by MaxEntScan or SpliceAI to impact splicing. This variant has a minor allele frequency in gnomAD v2.1.1 of 0.000008791 in the European non-Finnish population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as likely benign for autosomal dominant hereditary breast and pancreatic cancer and autosomal recessive FANCN based on the ACMG/AMP criteria applied as specified by the HBOP VCEP. (BP4, BP7)

ClinGen Evidence Repository → · reported verbatim, not re-tallied by Sugi Variant.

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 1.7	GERP 1.7, phastCons 1
Overall
CADD	4.561	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,974 alleles

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

Overall 0.000124% 2/1,614,022 alleles · very rare exomes 2/1,461,812 · genomes 0/152,210 · 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.Lys45=
Coding: c.135G>A
MANE Select: NM_024675
dbSNP: rs753270291
Type: single nucleotide variant
Location: chr16:23637926 (GRCh38)
Gene constraint: LOEUF 0.9 · pLI <0.01 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 54.07 · 4 PDB
Residue 45: the 'interaction with rad51' region; the 'required for its oligomerization and is important for its focal concentration at dna damage sites' 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

Also linked: hereditary neoplastic syndrome hereditary breast carcinoma

Similar variants

PALB2 p.Lys45Asn Conflicting classifications of pathogenicity ★ ⚠ same residue
PALB2 p.Lys45Gln Uncertain significance ★ ⚠ same residue
PALB2 p.Lys45Ter 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
PALB2 p.Glu3Ter 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-lys45 (accessed [today's date]).

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