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.Gln228*) 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 variant has not been reported in the literature in individuals affected with PALB2-related conditions. ClinVar contains an entry for this variant (Variation ID: 484222). For these reasons, this variant has been classified as Pathogenic.
Variant summary: PALB2 c.682C>T (p.Gln228X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251096 control chromosomes. c.682C>T has been reported in the literature in at least one individual affected with breast cancer (e.g. Yang_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four submitters, including one expert panel (ClinGen), have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
"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: PALB2Q228*PALB2Q228*SomaticNCBI Gene:79728|Show additional gene information Variant OverviewPALB2, a scaffolding protein involved in DNA repair, is altered in various cancers.The PALB2 Q228* 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) | 0.01 | -12 bp |
| Acceptor Gain (AG) | 0.0 | -493 bp |
| Donor Gain (DG) | 0.01 | 289 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)