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
The PALB2 D777N variant has not been functionally characterized. Its effect on PALB2 protein function remains unknown.
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Computational Analysis
Pathogenicity Predictions
SpliceAISpliceAI Scores
Window: ±500bp| Effect Type | Score | Position |
|---|---|---|
| Acceptor Loss (AL) | 0.01 | 134 bp |
| Donor Loss (DL) | 0.0 | -185 bp |
| Acceptor Gain (AG) | 0.0 | -94 bp |
| Donor Gain (DG) | 0.0 | -291 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 (c.2329G>A; p.D777N), not a null variant. Therefore, this criterion is not applied because the variant does not meet the requirement of a predicted loss-of-function variant.
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: no previously established pathogenic variant with the same amino acid change. 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 data on de novo occurrence. Therefore, this criterion is not applied because de novo status is not confirmed.
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 because functional study data are missing.
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). Modification Type: Disease-specific". The evidence for this variant shows: no case-control data. Therefore, this criterion is not applied because statistical evidence of enrichment in affected individuals is lacking.
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: no evidence it lies in a known hotspot or critical domain. Therefore, this criterion is not applied because the variant is not in a defined mutational hotspot or domain.
PM2 (Not Applied)
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: present in gnomAD at 4/251,432 alleles (MAF 0.00159%), which exceeds the ≤1/300,000 threshold. Therefore, this criterion is not applied because the allele frequency does not meet the rarity threshold.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Strong Strength: Strong Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". The evidence for this variant shows: no evidence of trans configuration with a pathogenic variant in a recessive context. Therefore, this criterion is not applied because PM3 scenarios are not met.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: it is a missense substitution without length change. Therefore, this criterion is not applied because there is no effect on 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 missense and not truncating. Therefore, this criterion is not applied because PM5 addresses truncating variants upstream of p.Tyr1183.
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 information on de novo status. Therefore, this criterion is not applied because assumed de novo status is not documented.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "Strong Strength: Strong LOD ≥1.26 or Bayes Factor (LR) ≥18:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied because family segregation analysis is lacking.
PP2 (Not Applied)
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: no gene-specific evidence supporting a low benign missense rate. Therefore, this criterion is not applied due to insufficient context.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting Protein: Do not use. RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing Modification Type: General recommendation". The evidence for this variant shows: SpliceAI predicts no impact on splicing. Therefore, this criterion is not applied because computational evidence does not indicate a deleterious effect on splicing.
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 patient phenotype provided. Therefore, this criterion is not applied because phenotype data are not available.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: no such reports exist. Therefore, this criterion is not applied because no reputable pathogenic assertion is available.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone GnomAD Filtering Allele Frequency >0.1% Modification Type: Disease-specific,Gene-specific". The evidence for this variant shows: allele frequency is 0.00159%, below the 0.1% threshold. Therefore, this criterion is not applied because the frequency does not exceed 0.1%.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong GnomAD Filtering Allele Frequency greater than expected for disease >.01% Modification Type: Disease-specific,Gene-specific". The evidence for this variant shows: allele frequency is 0.00159%, below the 0.01% threshold. Therefore, this criterion is not applied because the frequency does not exceed 0.01%.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Per Fanconi Anemia BS2 tables Modification Type: Disease-specific". The evidence for this variant shows: no observations in healthy adults per FA BS2 tables. Therefore, this criterion is not applied because no control data meeting BS2 are available.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied because such functional data are missing.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data to calculate LOD. Therefore, this criterion is not applied because segregation evidence is lacking.
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Supporting Apply to all missense variants. Modification Type: Gene-specific". The evidence for this variant shows: the variant is a missense substitution (D777N). Therefore, this criterion is applied at Supporting strength because it is a missense change 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 dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows: no data on cis/trans relationships with pathogenic variants. Therefore, this criterion is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without a known function." The evidence for this variant shows: it is not an in-frame indel. 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 Modification Type: General recommendation". The evidence for this variant shows: SpliceAI score 0.01, indicating no impact on splicing. Therefore, this criterion is applied at Supporting strength because RNA splicing prediction is not deleterious.
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 alternate molecular basis reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: no such benign assertions in ClinVar or literature. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Strong Strength: Strong BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality." The evidence for this variant shows: it is a missense change, not synonymous or intronic. Therefore, this criterion is not applied.