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 alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 745 of the PALB2 protein (p.Lys745Arg). This variant is present in population databases (rs142343372, gnomAD 0.02%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28944238). ClinVar contains an entry for this variant (Variation ID: 480232). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt PALB2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
The PALB2 c.2234A>G (p.Lys745Arg) variant has been reported in the published literature in individuals with colorectal cancer (PMID: 28944238 (2017)). Additionally, a functional study suggests that the variant is not damaging to protein function (PMID: 31636395 (2020)). The frequency of this variant in the general population, 0.00018 (3/16256 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
"This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (5 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 | 452 bp |
| Donor Loss (DL) | 0.0 | -386 bp |
| Acceptor Gain (AG) | 0.02 | 39 bp |
| Donor Gain (DG) | 0.0 | 356 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 (K745R), not a null variant. Therefore, this criterion is not applied because the variant does not meet the definition of a loss‐of‐function change under the PVS1 decision tree.
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 resulting in the same amino acid change K745R. Therefore, this criterion is not applied because there is no known pathogenic variant with the same amino acid substitution.
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 confirmation.
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 studies have been performed. Therefore, this criterion is not applied due to absence of functional 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) Modification Type: Disease-specific'. The evidence for this variant shows: no case-control or cohort data are available. Therefore, this criterion is not applied due to lack of statistical association data.
PM1 (Not Applied)
According to standard ACMG guidelines, the rule for PM1 is: 'Located in a mutational hot spot and/or well‐studied functional domain without benign variation'. The evidence for this variant shows: K745R falls outside any known mutational hotspot or characterized critical functional domain. Therefore, this criterion is not applied.
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: observed in gnomAD at MAF=0.00119% (3/251,494 alleles), exceeding the ≤1/300,000 threshold. Therefore, this criterion is not applied because the allele frequency is above the VCEP threshold for PM2_supporting.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength'. The evidence for this variant shows: no evidence of biallelic occurrence or trans observations in recessive cases. Therefore, this criterion is not applied.
PM4 (Not Applied)
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions or stop-loss variants'. The evidence for this variant shows: this is a missense substitution with no change in protein length. Therefore, this criterion is not applied.
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: K745R is not a truncating or frameshifting variant. Therefore, this criterion is not applied.
PM6 (Not Applied)
According to standard ACMG guidelines, the rule for PM6 is: 'Assumed de novo, 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 for PP1 is: '- **Strong Strength**: Strong LOD ≥1.26 or Bayes Factor (LR) ≥18:1; - **Moderate Strength**: Moderate LOD ≥0.60 or Bayes Factor ≥4:1; - **Supporting Strength**: Supporting LOD ≥0.30 or Bayes Factor ≥2:1'. The evidence for this variant shows: no family segregation data are available. 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 and where missense variants are a common mechanism of disease'. The evidence for this variant shows: PALB2 has known pathogenic and benign missense variants, but no gene‐specific rate data to support PP2. Therefore, this criterion is not applied.
PP3 (Not Applied)
According to VCEP guidelines, the rule for PP3 is: '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 impact on splicing (score=0.02). Therefore, this criterion is not applied because there is no computational evidence of splicing impact.
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 clinical phenotype or family history data linking to PALB2‐related disease. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source (e.g., ClinVar) has reported the variant as pathogenic'. The evidence for this variant shows: ClinVar reports are conflicting (Likely benign and VUS). 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 0.00119%, which is <0.1%. 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 0.00119%, which is <0.01%. Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: '- **Strong Strength**: Strong Per Fanconi Anemia BS2 tables'. The evidence for this variant shows: no observations in healthy homozygotes or other healthy adult data are available. Therefore, this criterion is not applied.
BS3 (Not Applied)
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established in vitro or in vivo functional studies show no damaging effect on protein function'. The evidence for this variant shows: no functional assays have been performed. Therefore, this criterion is not applied.
BS4 (Not Applied)
According to VCEP guidelines, the rule 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 data demonstrating non‐segregation. Therefore, this criterion is not applied.
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: 'Supporting Strength: Apply to all missense variants. Modification Type: Gene-specific'. The evidence for this variant shows: K745R is a missense variant. Therefore, this criterion is applied at Supporting strength because all PALB2 missense variants qualify under BP1.
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 in cis with a pathogenic variant in any inheritance pattern'. The evidence for this variant shows: no phase data with other 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: this is a single nucleotide missense change, not an in-frame indel in a repetitive region. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: 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 predicts minimal splicing impact (max score=0.02). Therefore, this criterion is applied at Supporting strength because computational splicing evidence is benign.
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 evidence of an alternate molecular diagnosis. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source (e.g., ClinVar) reports variant as benign'. The evidence for this variant shows: ClinVar entries are conflicting and not uniformly benign. 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'. The evidence for this variant shows: it is a missense substitution, not a silent or intronic variant. Therefore, this criterion is not applied.