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 (2 clinical laboratories)."
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 | 448 bp |
| Donor Loss (DL) | 0.0 | -17 bp |
| Acceptor Gain (AG) | 0.0 | 218 bp |
| Donor Gain (DG) | 0.0 | 36 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: "Use PALB2 PVS1 Decision Tree" (Very Strong Strength). The evidence for this variant shows: c.841A>G (p.I281V) is a missense change, not a null variant. Therefore, this criterion is not applied because PVS1 applies only to null variants per the PALB2 PVS1 Decision Tree.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: "Use PALB2 PS1 Splicing table" (Strong Strength). The evidence for this variant shows: there is no previously established pathogenic variant resulting in the same amino acid change p.I281V. Therefore, PS1 is not applied.
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 data are available. Therefore, PS2 is not applied.
PS3 (Not Applied)
According to standard ACMG guidelines, the rule for PS3 is: "Well-established 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 for p.I281V. Therefore, PS3 is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: "Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5)" (Strong Strength). The evidence for this variant shows: no case-control data are available. Therefore, PS4 is not applied.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or critical functional domain without benign variation." The evidence for this variant shows: p.I281V is not located in a known mutational hot spot or critical functional domain. Therefore, PM1 is not applied.
PM2 (Supporting)
According to VCEP guidelines, the rule for PM2 is: "Variant absent in gnomAD or present in ≤ 1/300,000 alleles" (Supporting Strength). The evidence for this variant shows: p.I281V is absent from gnomAD. Therefore, PM2 is applied at Supporting strength because the variant is absent from population databases.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: "Use Fanconi Anemia PM3 tables" (Supporting Strength). The evidence for this variant shows: no evidence of this variant observed in trans with a pathogenic variant in a recessive context. Therefore, PM3 is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes as a result of in-frame indels or stop-loss." The evidence for this variant shows: p.I281V is a missense variant without any change to protein length. Therefore, PM4 is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 is: "Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183, based on location of the most C-terminal known pathogenic variant, p.Tyr1183*" (Supporting Strength). The evidence for this variant shows: p.I281V is a missense change. Therefore, PM5 is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity." The evidence for this variant shows: no de novo data are available. Therefore, PM6 is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: "LOD ≥0.3 or Bayes Factor (LR) ≥2:1" (Supporting Strength). The evidence for this variant shows: no segregation data are available. Therefore, PP1 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 and where missense variants are a common mechanism of disease." The evidence for this variant shows: PALB2 has both missense and truncating pathogenic variants and the benign missense variation rate is not established. Therefore, PP2 is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: "Protein predictors should not be used; RNA: at least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing" (Supporting Strength). The evidence for this variant shows: SpliceAI predicts no impact on splicing. Therefore, PP3 is not applied.
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 phenotype or family history data provided. Therefore, PP4 is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic." The evidence for this variant shows: ClinVar reports VUS. Therefore, PP5 is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 is: "Allele frequency >0.1% in gnomAD" (Stand Alone Strength). The evidence for this variant shows: p.I281V is absent from gnomAD. Therefore, BA1 is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 is: "GnomAD Filtering Allele Frequency greater than expected for disease >0.01%" (Strong Strength). The evidence for this variant shows: p.I281V is absent from gnomAD. Therefore, BS1 is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: "Per Fanconi Anemia BS2 tables" (Strong Strength). The evidence for this variant shows: no observation in healthy individuals. Therefore, BS2 is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function." The evidence for this variant shows: no functional studies performed. Therefore, BS3 is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule for BS4 is: "LOD ≤ -1.28 or Bayes Factor ≤0.053:1" (Strong Strength). The evidence for this variant shows: no segregation data available. Therefore, BS4 is not applied.
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: "Apply to all missense variants" (Supporting Strength). The evidence for this variant shows: p.I281V is a missense variant, and PALB2 disease mechanism is loss of function. Therefore, BP1 is applied at Supporting strength because missense variants are less likely to be pathogenic.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in any disorder." The evidence for this variant shows: no such observations. Therefore, BP2 is not applied.
BP3 (Not Applied)
According to standard ACMG guidelines, the rule for BP3 is: "In-frame indels in repetitive region without functional domain." The evidence for this variant shows: p.I281V is a missense change. Therefore, BP3 is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Protein predictors not used; RNA: at least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing" (Supporting Strength). The evidence for this variant shows: SpliceAI predicts no splicing impact and protein predictors trend benign. Therefore, BP4 is applied at Supporting strength because multiple computational lines of evidence indicate no 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 data. Therefore, BP5 is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign." The evidence for this variant shows: ClinVar reports VUS. Therefore, BP6 is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: "Synonymous and deep intronic variants observed lack of RNA defect" (Supporting Strength). The evidence for this variant shows: p.I281V is not synonymous or intronic. Therefore, BP7 is not applied.