PALB2 c.3502G>T, p.Asp1168Tyr
NM_024675.4:c.3502G>T
Variant of Uncertain Significance (VUS)
PALB2 c.3502G>T (p.D1168Y) is a missense variant absent from population databases with no functional, segregation, or phenotype data to support pathogenicity, and in silico splicing predictors indicate no impact. It meets one supporting pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4), resulting in a classification of Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM2
BP1
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.3502G>T
Protein Change
D1168Y
Location
Exon 13
(Exon 13 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 1168 in gene PALB2
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.3502G>T
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
No evidence of other pathogenic variants at position 1168 in gene PALB2
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.197
0.197
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 3.72metasvm: Tmetalr: Tprimateai: T
Neutral: Show all
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PVS1 is: "Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength" (applicable to null variants). The evidence for this variant shows: missense change D1168Y, not a null variant. Therefore, this criterion is not applied.
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: no previously established pathogenic variant at codon 1168. 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". The evidence for this variant shows: no de novo data available. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
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 available. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared to controls". The evidence for this variant shows: no case-control or cohort data 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". The evidence for this variant shows: D1168Y is not located in a known hotspot or critical domain. 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: absent from gnomAD (MAF=0%). Therefore, this criterion is applied at Supporting strength because of absence from population databases.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for a recessive disorder". The evidence for this variant shows: not a recessive scenario. 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 indels or nonsense variants". The evidence for this variant shows: missense substitution without protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen". The evidence for this variant shows: no other pathogenic missense at D1168. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity". The evidence for this variant shows: no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members". The evidence for this variant shows: no segregation data available. 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 a low rate of benign missense variation and pathogenic missense variants are common". The evidence for this variant shows: insufficient data to assess missense constraint. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Protein: Do not use. RNA: At least one well-established in silico predictor shows impact on splicing". The evidence for this variant shows: SpliceAI predicts no impact on splicing. 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 phenotype data provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic". The evidence for this variant shows: not found in ClinVar. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone: GnomAD Filtering Allele Frequency >0.1%". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong: GnomAD Filtering Allele Frequency greater than expected for disease >0.01%". The evidence for this variant shows: absent from gnomAD. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong: Per Fanconi Anemia BS2 tables". The evidence for this variant shows: no healthy individual data. 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 on gene or gene product". The evidence for this variant shows: no functional studies. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong: LOD ≤ -1.28 or Bayes Factor ≤0.053:1". The evidence for this variant shows: no segregation or non-segregation data available. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Apply to all missense variants". The evidence for this variant shows: D1168Y is a missense substitution. Therefore, this criterion is applied at Supporting strength because it is a missense in a LOF gene.
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 dominant disorder". The evidence for this variant shows: no trans observation. 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". The evidence for this variant shows: missense substitution. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "RNA: At least one well-established in silico predictor shows no impact on splicing". The evidence for this variant shows: SpliceAI predicts no splicing impact (scores 0). Therefore, this criterion is applied at Supporting strength because of the lack of predicted splicing impact.
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 case. 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". The evidence for this variant shows: not in ClinVar. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Synonymous and deep intronic variants with no splice impact". The evidence for this variant shows: missense substitution. Therefore, this criterion is not applied.