PALB2 c.585A>T, p.Ile195=
NM_024675.4:c.585A>T
Likely Benign
This synonymous PALB2 variant c.585A>T shows no splicing impact by in silico analysis (BP4) and is reported benign by reputable sources (BP6). No pathogenic criteria are met. With two supporting benign criteria, the variant is classified as Likely Benign.
ACMG/AMP Criteria Applied
BP4
BP6
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.585A>T
Protein Change
I195=
Location
Exon 4
(Exon 4 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.585A>T
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00159%
Rare
Highest in Population
European (non-Finnish)
0.00352%
Rare
Global: 0.00159%
European (non-Finnish): 0.00352%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251432Alt: 4Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00159%, 4/251432 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00352%, 4/113724 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 7 submitter reviews in ClinVar
Submitter Breakdown
6 LB
1 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (1 clinical laboratories).
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: -0.01
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific) VCEP Guidelines
PVS1
PVS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PVS1 rule uses the PALB2 PVS1 Decision Tree (Gene-specific,Strength). This variant is synonymous (no predicted protein truncation) and does not meet criteria for PVS1. Therefore, PVS1 is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the PS1 rule refers to the PALB2 PS1 Splicing table (General recommendation). This variant does not create an amino acid change equivalent to a known pathogenic variant. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence with paternity and maternity confirmed. No de novo evidence is available. 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 on the gene or gene product. No functional data are available. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires significant case-control data with OR ≥3 and lower 95% CI ≥1.5. No such data exist for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hotspots or functional domains without benign variation. This synonymous variant is not in a reported hotspot. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2 Supporting strength applies to variants absent in gnomAD or present in ≤1/300,000 alleles. This variant is present in 4/251,432 alleles (>1 allele). Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines for Fanconi Anemia, PM3 applies to observed trans configuration with a pathogenic variant. No such data exist. 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 is a synonymous variant with no length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 Supporting applies to truncating variants upstream of known pathogenic variant p.Tyr1183. This variant is synonymous. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo cases without confirmation. No de novo data are available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies to segregation evidence with LOD or Bayes Factor thresholds. 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 with low benign variation. This variant is synonymous. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP3 requires multiple in silico tools predicting a deleterious effect. SpliceAI predicts no impact (score 0.01), and other tools are mixed with benign lean. No evidence of deleterious impact. Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 requires a patient phenotype specific for the gene. No phenotype data are provided. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 requires a reputable source reporting pathogenicity without available evidence. No such reports. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to standard ACMG guidelines, BA1 requires allele frequency >0.1% in general population. This variant has MAF 0.00159%, below threshold. Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 Strong applies to allele frequency >0.01%. This variant's frequency is 0.00159%, below threshold. Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines for Fanconi Anemia, BS2 applies to observation in healthy individuals. No such data. 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 available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies to lack of segregation with disease. No segregation data available. Therefore, BS4 is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, BP1 Supporting applies to all missense variants. This is synonymous. Therefore, BP1 is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when occurring in trans with a pathogenic variant. No such data. 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 is a SNV. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 Supporting strength (RNA): "At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing." SpliceAI predicts minimal impact (max score 0.01). Therefore, BP4 is applied at Supporting strength because computational evidence indicates no splicing effect.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant is found in a case with an alternate molecular cause. No such data. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6: "Reputable source reports variant as benign but evidence is not available to the laboratory for independent evaluation." ClinVar reports this variant as Likely benign (6 labs) and Benign (1 lab). Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 requires observed lack of aberrant RNA in assays for silent substitutions. No RNA assay data are available. Therefore, BP7 is not applied.