PALB2 c.2185_2186insA, p.Pro729HisfsTer16
NM_024675.4:c.2185_2186insA
Population Frequency
0.0 in 100,000
Rare
ClinVar Classification
Pathogenic
1 publications
REVEL Score
N/A
Not Available
COSMIC Recurrence
0 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
Genetic Information
Gene & Transcript Details
Gene
PALB2
Transcript
NM_024675.4
MANE Select
Total Exons
13
Strand
Reverse (−)
Reference Sequence
NC_000016.9
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_024675.3 | RefSeq Select | 13 exons | Reverse |
Variant Details
HGVS Notation
NM_024675.4:c.2185_2186insA
Protein Change
P729Hfs*16
Location
Exon 5
(Exon 5 of 13)
5'
Exon Structure (13 total)
3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 729 in gene PALB2
Variant interpretation based on transcript NM_024675.4
Clinical Evidence
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
1 publications
Pathogenic
Based on 4 submitter reviews in ClinVar
Submitter Breakdown
Pathogenic
Likely Pathogenic
VUS
Likely Benign
Benign
Publications
1 publications
Show publication details
Clinical Statement
This variant has been reported in ClinVar as Pathogenic (4 clinical laboratories).
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
No evidence of other pathogenic variants at position 729 in gene PALB2
Functional Studies
Summary
The PALB2 P729Hfs*16 variant is a truncating mutation in a tumor suppressor gene involved in DNA repair. Functional evidence indicates that truncating mutations in PALB2 can lead to the production of C-terminally truncated proteins, which are associated with an increased risk of breast cancer, including both estrogen receptor-positive and -negative types, as well as hereditary male breast cancer. This suggests a damaging effect of the variant.
Computational Evidence
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
VCEP Guidelines
PVS1
PVS1 (Very Strong)
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 frameshift insertion causing a premature termination codon at p.P729Hfs*16, not located in the terminal exon, consistent with loss-of-function. Therefore, this criterion is applied at Very Strong strength because the variant results in a null allele in a gene where loss of function is a known mechanism of disease.
PS1
PS1 (Not Applied)
Strength Modified
According to standard ACMG 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: it does not result in an amino acid change already known to be pathogenic. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied)
Strength Modified
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 or parental testing information is reported. Therefore, this criterion is not applied.
PS3
PS3 (Strong)
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: functional studies indicate that truncating PALB2 variants produce C-terminally truncated proteins with impaired DNA repair function and increased cancer risk. Therefore, this criterion is applied at Strong strength because well-established functional evidence demonstrates damaging effect.
PS4
PS4 (Not Applied)
Strength Modified
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)'. The evidence for this variant shows: no case-control data or statistical evidence are available. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied)
Strength Modified
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: it is a frameshift variant not mapped to a defined hot spot or functional domain beyond general LOF. Therefore, this criterion is not applied.
PM2
PM2 (Supporting)
Strength Modified
According to VCEP guidelines, the rule for PM2 is: 'Supporting Strength: Supporting Variant absent in gnomAD or present in ≤1/300,000 alleles'. The evidence for this variant shows: it is absent from population databases including gnomAD (MAF = 0). Therefore, this criterion is applied at Supporting strength because the variant is absent from controls.
PM3
PM3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: 'For recessive disorders, detected in trans with a pathogenic variant'. The evidence for this variant shows: no information on zygosity or trans configuration with another pathogenic variant. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: 'Protein length changes due to in-frame deletions/insertions in non-repeat regions'. The evidence for this variant shows: it is a frameshift insertion, not an in-frame change. Therefore, this criterion is not applied.
PM5
PM5 (Supporting)
Strength Modified
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: the premature stop at p.*729 is upstream of p.Tyr1183. Therefore, this criterion is applied at Supporting strength because it meets the gene-specific location rule.
PM6
PM6 (Not Applied)
Strength Modified
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 information is available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: 'Cosegregation with disease in multiple affected family members'. The evidence for this variant shows: no segregation data are reported. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: 'Missense variant in a gene with low rate of benign missense variation'. The evidence for this variant shows: it is a frameshift insertion, not a missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied)
Strength Modified
According to VCEP guidelines, the rule for PP3 is: 'Supporting Strength: Protein predictors not used; RNA: at least one well-established in silico predictor shows impact on splicing'. The evidence for this variant shows: SpliceAI maximum score 0.02 indicates no splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied)
Strength Modified
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 detailed phenotype or family history data. Therefore, this criterion is not applied.
PP5
PP5 (Supporting)
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: ClinVar entries from four clinical laboratories classify it as Pathogenic without primary data. Therefore, this criterion is applied at Supporting strength because of the reputable multiple sources.
BA1
BA1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: 'Allele frequency is >5% in general population'. The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS1 is: 'Allele frequency greater than expected for disorder'. The evidence for this variant shows: MAF = 0%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS2 is: 'Observed in a healthy adult with full penetrance expected at an early age'. The evidence for this variant shows: no data on observation in healthy individuals. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: 'Well-established functional studies show no damaging effect'. The evidence for this variant shows: functional studies indicate damaging effect. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: 'Lack of segregation in affected members of a family'. The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: 'Missense variant in a gene for which primarily truncating variants cause disease'. The evidence for this variant shows: it is a truncating variant. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: 'Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder'. The evidence for this variant shows: no such observation data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: 'In-frame deletions/insertions in repetitive regions without a known function'. The evidence for this variant shows: it is frameshift and not in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: 'Supporting Strength: RNA: at least one well-established in silico predictor shows no impact on splicing'. The evidence for this variant shows: SpliceAI maximum score 0.02 indicates no splicing impact. Therefore, this criterion is applied at Supporting strength because no splicing defect is predicted.
BP5
BP5 (Not Applied)
Strength Modified
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 alternate basis reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: 'Reputable source reports variant as benign without available evidence'. The evidence for this variant shows: no reputable source reports it as benign. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied)
Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: 'Synonymous variants with no predicted splice impact'. The evidence for this variant shows: it is not synonymous. Therefore, this criterion is not applied.