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"This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories) and as Likely benign (1 clinical laboratories)."
COSMIC Somatic Evidence
OpenFunctional Impact & Domains
Functional Domain
Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.03 | -367 bp |
| Donor Loss (DL) | 0.08 | -2 bp |
| Acceptor Gain (AG) | 0.0 | 89 bp |
| Donor Gain (DG) | 0.22 | -108 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule/finding 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 (Q838E) and not a predicted loss-of-function variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule/finding for PS1 is: "Strong Strength: Strong Use PALB2 PS1 Splicing table Modification Type: General recommendation". The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same amino acid change. Therefore, this criterion is not applied.
PS2 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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 data are available. Therefore, this criterion is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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 studies have been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule/finding 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 are available. Therefore, this criterion is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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: Q838E is not located in a known mutational hotspot or critical functional domain. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule/finding 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: MAF = 0.00318% (1/31406 alleles), which exceeds 1/300,000 (≈0.00033%). Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule/finding for PM3 is: "Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". The evidence for this variant shows: no data on trans configuration with a pathogenic variant in a recessive context. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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: it is a single amino acid substitution, not a length-altering variant. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule/finding 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 change, not a truncating variant upstream of p.Tyr1183. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo data are available. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule/finding for PP1 is: "Supporting Strength: Supporting LOD ≥0.3 or Bayes Factor (LR) ≥2:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data are available. Therefore, this criterion is not applied.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease". The evidence for this variant shows: PALB2 has both pathogenic missense and truncating variants, and there is insufficient evidence to meet PP2. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule/finding for PP3 is: "Supporting Strength: Supporting RNA: At least one well-established in silico predictor shows impact on splicing". The evidence for this variant shows: SpliceAI max score is 0.22 (low), indicating no significant splicing impact. Therefore, this criterion is not applied.
PP4 (Not Applied)
According to standard ACMG guidelines, the rule/finding 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 phenotype or family history data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for PP5 is: "Reputable source reports variant as pathogenic, but evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: ClinVar includes only VUS and one likely benign entry, with no established pathogenic classification. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule/finding for BA1 is: "Stand Alone Strength: Stand Alone GnomAD Filtering Allele Frequency >0.1%". The evidence for this variant shows: MAF = 0.00318% (<0.1%). Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule/finding for BS1 is: "Strong Strength: Strong GnomAD Filtering Allele Frequency greater than expected for disease >0.01%". The evidence for this variant shows: MAF = 0.00318% (<0.01%). Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule/finding for BS2 is: "Strong Strength: Strong Per Fanconi Anemia BS2 tables Modification Type: Disease-specific". The evidence for this variant shows: no data on observation in healthy individuals beyond population frequency. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BS3 is: "Well‐established in vitro or in vivo functional studies show no damaging effect on protein function or splicing". The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule/finding for BS4 is: "Strong Strength: Strong LOD ≤ -1.28 or Bayes Factor (LR) ≤ 0.053:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation or non-segregation data. Therefore, this criterion is not applied.
BP1 (Supporting)
According to VCEP guidelines, the rule/finding for BP1 is: "Supporting Strength: Supporting Apply to all missense variants Modification Type: Gene-specific". The evidence for this variant shows: Q838E is a missense change. Therefore, this criterion is applied at Supporting strength.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP2 is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder". The evidence for this variant shows: no data on trans observations. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP3 is: "In‐frame deletions/insertions in a repetitive region without a known function". The evidence for this variant shows: it is a missense variant, not an in‐frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule/finding for BP4 is: "Supporting Strength: Supporting Protein: Do not use. RNA: At least one well-established in silico predictor shows no impact on splicing". The evidence for this variant shows: SpliceAI max score 0.22, indicating no splicing impact. Therefore, this criterion is applied at Supporting strength.
BP5 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP5 is: "Variant found in a case with an alternate molecular basis for disease". The evidence for this variant shows: no data of alternate molecular basis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule/finding for BP6 is: "Reputable source reports variant as benign, but evidence is not available to the laboratory to perform an independent evaluation". The evidence for this variant shows: ClinVar includes no established benign classification from a reputable source. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule/finding for BP7 is: "Supporting Strength: Supporting BP7: Synonymous and deep intronic Variants Observed Lack of aberrant RNA defect". The evidence for this variant shows: it is a missense change, not synonymous or deep intronic. Therefore, this criterion is not applied.