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 isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 654 of the PALB2 protein (p.Ile654Val). This variant is present in population databases (rs749842477, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or esophageal cancer (PMID: 21279724, 27648926). ClinVar contains an entry for this variant (Variation ID: 234115). 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.
This missense variant replaces isoleucine with valine at codon 654 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 27648926) and in an individual affected with esophageal squamous cell carcinoma (PMID: 21279724). This variant has been identified in 2/251154 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Variant summary: PALB2 c.1960A>G (p.Ile654Val) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251154 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1960A>G has been reported in the literature in the heterozygous state in at least 1 individual affected with male breast cancer and at least 1 individual affected with esophageal squamous cell carcinoma (example, Akbari_2011, Silvestri_2017). These reports do not provide unequivocal conclusions about association of the variant with breast or other PALB2-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21279724, 27648926). ClinVar contains an entry for this variant (Variation ID: 234115). Based on the evidence outlined above, the variant was classified as uncertain significance.
"This variant has been reported in ClinVar as Likely benign (1 clinical laboratories) and as Uncertain significance (8 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 | -235 bp |
| Donor Loss (DL) | 0.0 | 3 bp |
| Acceptor Gain (AG) | 0.01 | 136 bp |
| Donor Gain (DG) | 0.0 | 82 bp |
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1 (Not Applied)
According to VCEP guidelines, the rule for PVS1 is: 'Null Variant (nonsense, frameshift, start codon, splicing +1/2, startgain, single or multi-exon deletion) in a gene where LOF is a known mechanism of disease.' The evidence for this variant shows: it is a missense change (p.I654V), not a null variant. Therefore, this criterion is not applied.
PS1 (Not Applied)
According to VCEP guidelines, the rule for PS1 is: 'Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.' The evidence for this variant shows: no previously established pathogenic variant with the same I654V amino acid change. Therefore, this criterion 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 available. Therefore, this criterion 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 characterization has been performed. Therefore, this criterion is not applied.
PS4 (Not Applied)
According to VCEP guidelines, the rule for PS4 is: 'Case-control studies; p-value ≤.05 AND (OR ≥3 or lower 95% CI ≥1.5).' The evidence for this variant shows: no case-control data available. Therefore, this criterion 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: I654V is not in a known mutational hot spot or critical domain. Therefore, this criterion is not applied.
PM2 (Not Applied)
According to VCEP guidelines, the rule for PM2 (Supporting) is: 'Variant absent in gnomAD or present in ≤1/300,000 alleles.' The evidence for this variant shows: present in 2/251,154 alleles (MAF=0.000796%), which exceeds 1/300,000. Therefore, this criterion is not applied.
PM3 (Not Applied)
According to VCEP guidelines, the rule for PM3 is: 'Detected in trans with a pathogenic variant in recessive condition per Fanconi Anemia PM3 tables.' The evidence for this variant shows: no trans observations with a pathogenic PALB2 variant. 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 in a non-repeat region or stop-loss.' The evidence for this variant shows: it is a single amino acid substitution, not an in-frame indel. Therefore, this criterion is not applied.
PM5 (Not Applied)
According to VCEP guidelines, the rule for PM5 (Supporting) is: '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 and not truncating. 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 such data. Therefore, this criterion is not applied.
PP1 (Not Applied)
According to VCEP guidelines, the rule for PP1 is: 'Segregation data with LOD or Bayes Factor thresholds.' The evidence for this variant shows: no segregation studies reported. 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 low rate of benign missense variation and where missense variants are a common mechanism.' The evidence for this variant shows: PALB2’s missense constraint is not established as high specificity; VCEP does not specify 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 in silico predictor shows impact on splicing.' The evidence for this variant shows: SpliceAI predicts no impact on splicing (0.01). Therefore, this criterion 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 gene.' The evidence for this variant shows: no phenotype data provided. Therefore, this criterion is not applied.
PP5 (Not Applied)
According to standard ACMG guidelines, the rule for PP5 is: 'Reputable source reports variant as pathogenic without evidence.' The evidence for this variant shows: ClinVar submissions are uncertain or likely benign; no reputable pathogenic assertion. Therefore, this criterion is not applied.
BA1 (Not Applied)
According to VCEP guidelines, the rule for BA1 (Stand Alone) is: 'GnomAD Filtering Allele Frequency >0.1%.' The evidence for this variant shows: MAF=0.000796% (<0.1%). Therefore, this criterion is not applied.
BS1 (Not Applied)
According to VCEP guidelines, the rule for BS1 (Strong) is: 'GnomAD Filtering Allele Frequency greater than expected for disease >0.01%.' The evidence for this variant shows: MAF=0.000796% (<0.01%). Therefore, this criterion is not applied.
BS2 (Not Applied)
According to VCEP guidelines, the rule for BS2 is: 'Observed in healthy adult individuals per Fanconi Anemia BS2 tables.' The evidence for this variant shows: no such observations reported. 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: 'LOD ≤ -1.28 or Bayes Factor ≤ 0.053 indicating lack of segregation.' The evidence for this variant shows: no segregation analyses. Therefore, this criterion is not applied.
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 (Supporting) is: 'Apply to all missense variants.' The evidence for this variant shows: it is a missense change (p.I654V). Therefore, this criterion is applied at Supporting strength because the variant is missense and VCEP specifies BP1 for all missense variants.
BP2 (Not Applied)
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant in a dominant gene or cis with another pathogenic variant.' The evidence for this variant shows: no such observations. 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.' The evidence for this variant shows: it is a missense change, not an in-frame indel. Therefore, this criterion is not applied.
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 (Supporting) is: '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 no significant impact on splicing (max score 0.01). Therefore, this criterion is applied at Supporting strength because computational splicing analysis shows no predicted 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 case reported. Therefore, this criterion is not applied.
BP6 (Not Applied)
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without evidence.' The evidence for this variant shows: no such assertion. Therefore, this criterion is not applied.
BP7 (Not Applied)
According to VCEP guidelines, the rule for BP7 is: 'Synonymous and deep intronic variants with observed lack of RNA defect.' The evidence for this variant shows: it is a missense variant. Therefore, this criterion is not applied.