Genetic Information
Gene & Transcript Details
| ID | Status | Details |
|---|---|---|
| NM_024675.4 | MANE Select | 4008 nt | 154–3714 |
| NM_024675.3 | RefSeq Select | 4069 nt | 201–3761 |
Variant Details
Clinical & Population Data
Population Frequency
gnomADClinVar
OpenIn summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects PALB2 function (PMID: 31636395, 31757951). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PALB2 protein function. ClinVar contains an entry for this variant (Variation ID: 187262). This missense change has been observed in individual(s) with breast cancer (PMID: 30638972). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with asparagine, which is neutral and polar, at codon 944 of the PALB2 protein (p.Ile944Asn).
"This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen expert panel."
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Error in OpenAI Consolidation. OncoKB: PALB2I944NPALB2I944NSomaticNCBI Gene:79728|Show additional gene information Variant OverviewPALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.The PALB2 I944N mutation has not specifically been reviewed by the OncoKB team, and therefore its biological significance is unknown. JAX-CKB: PALB2 I944N lies within WD repeat 2 of the Palb2 protein (UniProt.org). I944N confers a loss of function to the Palb2 protein as demonstrated by decreased protein stability (PMID: 31757951), reduced Brca2 and Rad51 binding, recruitment to DNA damage sites, and Rad51 foci formation, aberrant cytosolic accumulation (PMID: 31636395), and loss of homology-directed DNA repair activity in cultured cells (PMID: 31636395, PMID: 31757951).
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 67 bp |
| Donor Loss (DL) | 0.0 | -467 bp |
| Acceptor Gain (AG) | 0.01 | 82 bp |
| Donor Gain (DG) | 0.0 | -3 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PS3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
BP4 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)