PALB2 c.3351-16_3351-14del, p.?
NM_024675.4:c.3351-16_3351-14del
Variant of Uncertain Significance (VUS)
This intronic deletion is absent from population databases and shows no predicted impact on splicing (PM2_Supporting, BP4_Supporting). No other evidence supports pathogenicity or benign impact, resulting in conflicting supporting-level evidence and a classification of Variant of Uncertain Significance.
ACMG/AMP Criteria Applied
PM2
BP4
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.3351-16_3351-14del
Protein Change
?
Location
Exon 12
(Exon 12 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.3351-16_3351-14del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Population Frequency
Global Frequency
0.0 in 100,000
Extremely Rare
Global: 0.0%
0%
0.05%
0.1%
1%
5%
10%+
ACMG Criteria Applied
PM2
This variant is not present in gnomAD (PM2 criteria applies).
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.30
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PVS1 rule applies to null variants in PALB2 per the PVS1 decision tree. The evidence for this variant shows it is a small intronic deletion outside canonical splice sites, not predicted to cause loss of function. Therefore, this criterion is not applied at any strength because the variant does not meet PVS1 requirements.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant. The evidence for this variant shows no change in protein sequence is predicted. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies to confirmed de novo variants. No de novo data are available for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies showing a damaging effect. No functional studies have been performed for this variant. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 applies to case-control data meeting specific statistical thresholds. No case-control or cohort data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants located in mutational hotspots or critical functional domains without benign variation. This variant is intronic outside known functional domains. Therefore, PM1 is not applied.
PM2
PM2 (Supporting) Strength Modified
According to VCEP guidelines, PM2: Supporting Variant absent in gnomAD or present in ≤ 1/300,000 alleles. The evidence for this variant shows it is not found in gnomAD (MAF=0%). Therefore, PM2 is applied at Supporting strength because the variant is absent from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive inheritance contexts with trans observations. No recessive or in trans data are available for this variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes due to in-frame indels or stop-loss. This variant is intronic and does not affect protein length. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to frameshifting or truncating variants with premature stop codons upstream of known pathogenic variants. This variant is intronic and does not create a termination codon. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without parental confirmation. There is no data suggesting de novo occurrence. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies for segregation data in families. No segregation data are available. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies to missense variants in genes where benign missense variants are rare. This variant is intronic and not a missense change. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 applies when in silico tools predict impact on splicing or protein. SpliceAI predicts no impact (max score 0.02) and other predictors are benign. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies to highly specific phenotypes. No patient phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies to reputable source assertions of pathogenicity. This variant is not in ClinVar or similar databases. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies for allele frequency >0.1% in gnomAD. This variant is absent from population databases. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 applies for allele frequency greater than expected for disease (>0.01%). This variant is absent in gnomAD. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies for observations in healthy adults per Fanconi Anemia BS2 tables. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 requires well-established functional studies showing no damaging effect. No functional data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for lack of segregation (LOD≤–1.28). No segregation data are available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 applies to all missense variants in certain contexts. This variant is intronic. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when observations in trans with a pathogenic variant for a dominant disorder. No such data exist. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This variant is intronic. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4: RNA: at least one well-established in silico predictor shows no impact on splicing. SpliceAI predicts no splicing impact (max score 0.02) and other predictors are benign. Therefore, BP4 is applied at Supporting strength because computational evidence supports no impact.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant found in a gene for which alternate molecular basis is established. Not applicable here. Therefore, BP5 is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP6 applies to reputable source assertions of benign impact. None exist. Therefore, BP6 is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or deep intronic variants with observed lack of RNA defect. No RNA assay data are available. Therefore, BP7 is not applied.