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
Open""
COSMIC Somatic Evidence
Open
Functional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.0 | -47 bp |
| Donor Loss (DL) | 0.0 | 18 bp |
| Acceptor Gain (AG) | 0.17 | 44 bp |
| Donor Gain (DG) | 0.13 | -117 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Very Strong Strength: Very Strong Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: it is a missense change (W877C), not a null variant. Therefore, this criterion is not applied because the variant does not meet the null variant requirement for loss-of-function.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Strong Use PALB2 PS1 Splicing table Modification Type: General recommendation". The evidence for this variant shows: it does not result in the same amino acid change as a previously established pathogenic variant. Therefore, this criterion is not applied because there is no matching pathogenic amino acid change.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". The evidence for this variant shows: no de novo or parental testing data are available. Therefore, this criterion is not applied due to lack of de novo data.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product". The evidence for this variant shows: no functional characterization has been performed. Therefore, this criterion is not applied due to absence of functional study data.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Strong Strength: Strong Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5)". The evidence for this variant shows: no case-control data. Therefore, this criterion is not applied because no statistical association studies are available.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical and well-established functional domain without benign variation". The evidence for this variant shows: location and domain data are unavailable. Therefore, this criterion is not applied due to insufficient domain information.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Supporting Strength: Supporting Variant absent in gnomAD or present in ≤ 1/300,000 alleles Modification Type: Gene-specific,Strength". The evidence for this variant shows: the variant is not present in gnomAD (MAF = 0%). Therefore, this criterion is applied at Supporting strength because the variant is absent from population databases as specified.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Strong/Moderate/Supporting Strength: Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". The evidence for this variant shows: no data on trans phase with a pathogenic variant in recessive disease context. Therefore, this criterion is not applied due to lack of segregation or trans observation data.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants". The evidence for this variant shows: this is a missense change, not an in-frame indel. Therefore, this criterion is not applied because it does not alter protein length.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Supporting Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183". The evidence for this variant shows: it is a missense variant, not a truncating variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong Strength: LOD or Bayes Factor thresholds for segregation". The evidence for this variant shows: no familial segregation data. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation or where missense is a common mechanism of disease". The evidence for this variant shows: no specific data on benign variation rate in PALB2. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein: Do not use. RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing". The evidence for this variant shows: SpliceAI predicts no splicing impact and protein predictors are mixed. Therefore, this criterion is not applied because no in silico evidence of splicing impact is present.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology". The evidence for this variant shows: no specific phenotype data. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic". The evidence for this variant shows: not found in ClinVar or other databases. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone GnomAD Filtering Allele Frequency >0.1%". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong GnomAD Filtering Allele Frequency greater than expected for disease >0.01%". The evidence for this variant shows: allele frequency is 0%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong/Moderate/Supporting Strength: Per Fanconi Anemia BS2 tables". The evidence for this variant shows: no observation in healthy adults. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect". The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong/Moderate/Supporting Strength: LOD or Bayes Factor thresholds for lack of segregation". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Supporting Apply to all missense variants". The evidence for this variant shows: it is a missense change (W877C). Therefore, this criterion is applied at Supporting strength because it is a missense variant in PALB2.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant autosomal dominant gene". The evidence for this variant shows: no trans observations with another pathogenic variant. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in repetitive regions without a known function". The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting • Protein: Do not use. RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing". The evidence for this variant shows: SpliceAI score 0.17 (no splicing impact) and mixed protein predictions. Therefore, this criterion is applied at Supporting strength because in silico RNA predictions show no splicing impact.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no such cases reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports as benign". The evidence for this variant shows: no such report. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Supporting Strength: Synonymous and deep intronic variants with observed lack of RNA defect". The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied.