PALB2 c.3252G>A, p.Ser1084=
NM_024675.4:c.3252G>A
COSMIC ID: COSM5342728
Likely Benign
This synonymous PALB2 variant (c.3252G>A; S1084=) shows no predicted impact on splicing or protein function and is reported as benign by reputable sources. Two supporting benign criteria (BP4, BP6) yield a final classification of 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.3252G>A
Protein Change
S1084=
Location
Exon 12
(Exon 12 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM5342728
Variant interpretation based on transcript NM_024675.4
Genome Browser
Loading genome browser...
HGVS InputNM_024675:c.3252G>A
Active Tracks
ConservationRefSeqClinVargnomAD
Navigation tips: Use mouse to drag and zoom. Click on features for details.
Clinical Data
Global Frequency
0.00283%
Rare
Highest in Population
European (non-Finnish)
0.00542%
Rare
Global: 0.00283%
European (non-Finnish): 0.00542%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282858Alt: 8Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00283%, 8/282858 alleles, homozygotes = 0) and at a higher frequency in the European (non-Finnish) population (MAF= 0.00542%, 7/129172 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
4 publications
Likely Benign
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
6 LB
2 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (4)
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitter to LOVD: Marc Tischkowitz.
This 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.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (6 clinical laboratories) and as Benign (2 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: -0.17
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: "Very Strong Strength: Very Strong Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: It is a synonymous (S1084=) change with no predicted protein truncation. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Strength: Strong Use PALB2 PS1 Splicing table Modification Type: General recommendation". The evidence for this variant shows: It does not result in an amino acid change matching a known pathogenic missense. 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 parental testing or de novo data are 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 have been performed. Therefore, this criterion is not applied.
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 or case prevalence data exist. 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 synonymous change not in a defined functional domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) 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 Modification Type: Gene-specific,Strength". The evidence for this variant shows: It has a maximum allele frequency of 0.00542% in Non-Finnish Europeans, exceeding the ≤0.00033% threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Supporting Strength: Supporting Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". The evidence for this variant shows: No data on trans occurrence with a pathogenic variant in a recessive context. 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 as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants." The evidence for this variant shows: It is synonymous with no protein length change. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) 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: It is synonymous, not truncating or frameshifting. 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 parental or de novo assumptions are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting Strength: Supporting LOD ≥0.3 or Bayes Factor ≥2:1 Modification Type: Gene-specific". The evidence for this variant shows: No segregation data are 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 for which primarily truncating variants are known to cause disease." The evidence for this variant shows: It is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing." The evidence for this variant shows: SpliceAI predicts no impact on splicing (max score 0.16). 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 highly specific for a disease with a single genetic etiology." The evidence for this variant shows: No specific phenotype information is available. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
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: All reputable sources report benign. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 is: "Stand Alone Strength: Stand Alone GnomAD Filtering Allele Frequency >0.1%." The evidence for this variant shows: Maximum allele frequency is 0.00542%, below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: Strong GnomAD Filtering Allele Frequency greater than expected for disease >0.01%." The evidence for this variant shows: Maximum allele frequency is 0.00542%, below 0.01%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Strength: Strong Per Fanconi Anemia BS2 tables Modification Type: Disease-specific". The evidence for this variant shows: No data on occurrence in unaffected individuals or homozygotes. 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 protein function." The evidence for this variant shows: No functional studies have been conducted. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong LOD ≤ -1.28 or Bayes Factor ≤0.053:1 Modification Type: Gene-specific". The evidence for this variant shows: No segregation data demonstrating lack of cosegregation. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Supporting Apply to all missense variants." The evidence for this variant shows: It is synonymous, not missense. 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 dominant disorder." The evidence for this variant shows: No trans data with pathogenic variants. 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 a repetitive region without a known function." The evidence for this variant shows: It is a single-nucleotide synonymous change. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting 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 splicing impact (max score 0.16) and CADD score is –0.17. Therefore, this criterion is applied at Supporting strength.
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 molecular basis information is available. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source recently reports variant as benign, but evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: ClinVar reports Likely benign (6 labs) and Benign (2 labs) without accessible underlying data. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Strong/Moderate/Supporting Strength: Observed lack of aberrant RNA defect for silent substitutions and intronic variants." The evidence for this variant shows: Only in silico splicing predictions are available, no RNA assay data. Therefore, this criterion is not applied.