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
OpenThis sequence change creates a premature translational stop signal (p.Glu178Asnfs*15) in the PALB2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PALB2 are known to be pathogenic (PMID: 17200668, 17200671, 17200672, 24136930, 25099575). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28779002). ClinVar contains an entry for this variant (Variation ID: 580962). For these reasons, this variant has been classified as Pathogenic.
The c.532delG pathogenic mutation, located in coding exon 4 of the PALB2 gene, results from a deletion of one nucleotide at nucleotide position 532, causing a translational frameshift with a predicted alternate stop codon (p.E178Nfs*15). This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med, 2021 02;384:428-439). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
"This variant has been reported in ClinVar as Pathogenic (5 clinical laboratories) and as Pathogenic 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: PALB2E178Nfs*15PALB2E178Nfs*15SomaticNCBI Gene:79728|Show additional gene information Variant OverviewPALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.The PALB2 E178Nfs*15 is a truncating mutation in a tumor suppressor gene, and therefore is likely oncogenic.Hide mutation effect description The mutation effect description for truncating mutations in PALB2 is: PALB2 truncating mutations can form several forms of C-terminally truncated PALB2 protein and are found in breast cancers. As such, PALB2 is considered a rare breast cancer susceptibility gene. In patient studies, PALB2 truncation mutations were shown to significantly increase the risk of breast cancer, with similar risks for estrogen receptor-positive and -negative breast cancer. PALB2 truncation mutations have also been found in cases of hereditary male breast cancer (PMID: 28858227, 18053174, 25529982, 29484706, 28279176, 28779002). JAX-CKB: No results found
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | 289 bp |
| Donor Loss (DL) | 0.0 | -161 bp |
| Acceptor Gain (AG) | 0.0 | 140 bp |
| Donor Gain (DG) | 0.05 | 140 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PS3 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PM2 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)
PP5 (Unknown (Pre-LLM))
From pre-LLM assessment (LLM Failed)