PALB2 c.2329G>A, p.Asp777Asn
NM_024675.4:c.2329G>A
COSMIC ID: COSM1219154
Variant of Uncertain Significance (VUS)
This legacy system is being phased out as Project HERA V3 is rolled out.
ACMG/AMP Criteria Applied
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.2329G>A
Protein Change
D777N
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 777 in gene PALB2
Alternate Identifiers
COSM1219154
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.2329G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00159%
Rare
Highest in Population
East Asian
0.0109%
Low Frequency
Global: 0.00159%
East Asian: 0.0109%
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 East Asian population (MAF= 0.0109%, 2/18394 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
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 777 in gene PALB2
Functional Summary
The PALB2 D777N variant has not been functionally characterized. Its effect on PALB2 protein function remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -1.71polyphen_prediction: benignmetasvm: 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: "Very Strong Strength: Very Strong Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: it is a missense change (c.2329G>A; p.D777N), not a null variant. Therefore, this criterion is not applied because the variant does not meet the requirement of a predicted loss-of-function variant.
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: no previously established pathogenic variant with the same amino acid change. Therefore, this criterion is not applied because there is no matching pathogenic amino acid change.
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 data on de novo occurrence. Therefore, this criterion is not applied because de novo status is not confirmed.
PS3
PS3 (Not Applied) Strength Modified
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: no functional characterization has been performed. Therefore, this criterion is not applied because functional study data are missing.
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). Modification Type: Disease-specific". The evidence for this variant shows: no case-control data. Therefore, this criterion is not applied because statistical evidence of enrichment in affected individuals is lacking.
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: no evidence it lies in a known hotspot or critical domain. Therefore, this criterion is not applied because the variant is not in a defined mutational hotspot or domain.
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: present in gnomAD at 4/251,432 alleles (MAF 0.00159%), which exceeds the ≤1/300,000 threshold. Therefore, this criterion is not applied because the allele frequency does not meet the rarity threshold.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Strong Strength: Strong Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". The evidence for this variant shows: no evidence of trans configuration with a pathogenic variant in a recessive context. Therefore, this criterion is not applied because PM3 scenarios are not met.
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 a missense substitution without length change. Therefore, this criterion is not applied because there is no effect on protein length.
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 missense and not truncating. Therefore, this criterion is not applied because PM5 addresses truncating variants upstream of p.Tyr1183.
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 information on de novo status. Therefore, this criterion is not applied because assumed de novo status is not documented.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Strong Strength: Strong LOD ≥1.26 or Bayes Factor (LR) ≥18:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied because family segregation analysis is lacking.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene that has a low rate of benign missense variation and where missense is a common mechanism of disease." The evidence for this variant shows: no gene-specific evidence supporting a low benign missense rate. Therefore, this criterion is not applied due to insufficient context.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Supporting Protein: Do not use. RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows impact on splicing Modification Type: General recommendation". The evidence for this variant shows: SpliceAI predicts no impact on splicing. Therefore, this criterion is not applied because computational evidence does not indicate a deleterious effect on splicing.
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 patient phenotype provided. Therefore, this criterion is not applied because phenotype data are not available.
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: no such reports exist. Therefore, this criterion is not applied because no reputable pathogenic assertion is available.
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% Modification Type: Disease-specific,Gene-specific". The evidence for this variant shows: allele frequency is 0.00159%, below the 0.1% threshold. Therefore, this criterion is not applied because the frequency does not exceed 0.1%.
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 >.01% Modification Type: Disease-specific,Gene-specific". The evidence for this variant shows: allele frequency is 0.00159%, below the 0.01% threshold. Therefore, this criterion is not applied because the frequency does not exceed 0.01%.
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 observations in healthy adults per FA BS2 tables. Therefore, this criterion is not applied because no control data meeting BS2 are available.
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 or splicing." The evidence for this variant shows: no functional studies performed. Therefore, this criterion is not applied because such functional data are missing.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong Strength: Strong LOD ≤ -1.28 or Bayes Factor (LR) ≤.053:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data to calculate LOD. Therefore, this criterion is not applied because segregation evidence is lacking.
BP1
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: "Supporting Strength: Supporting Apply to all missense variants. Modification Type: Gene-specific". The evidence for this variant shows: the variant is a missense substitution (D777N). Therefore, this criterion is applied at Supporting strength because it is a missense change in PALB2.
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, or observed in cis with a pathogenic variant in any inheritance pattern." The evidence for this variant shows: no data on cis/trans relationships 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 not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: Supporting • Protein: Do not use. RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing Modification Type: General recommendation". The evidence for this variant shows: SpliceAI score 0.01, indicating no impact on splicing. Therefore, this criterion is applied at Supporting strength because RNA splicing prediction is not deleterious.
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 alternate molecular 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 recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The evidence for this variant shows: no such benign assertions in ClinVar or literature. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Strong Strength: Strong BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. May reduce weight applied depending on assay quality." The evidence for this variant shows: it is a missense change, not synonymous or intronic. Therefore, this criterion is not applied.