PALB2 c.2329G>A, p.Asp777Asn
NM_024675.4:c.2329G>A
COSMIC ID: COSM1219154
Variant of Uncertain Significance (VUS)
PALB2 D777N is classified as Likely Benign based on two supporting benign criteria (BP1, BP4) under VCEP guidelines. The variant is a missense change not affecting splicing, absent strong pathogenic evidence, with population frequency below benign thresholds.
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
1 publications
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
5 VUS
3 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (1)
The PALB2 c.2329G>A (p.Asp777Asn) variant has been reported in the published literature in individuals affected with breast and/or ovarian cancer (PMID: 30309218 (2018)), as well as colorectal cancer (PMID: 28944238 (2017), 33309985 (2020)). It has also been identified in affected and reportedly healthy individuals in large-scale breast cancer association studies (PMIDs: 30287823 (2018), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (5 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
No evidence of other pathogenic variants at position 777 in gene PALB2
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: "Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength." The evidence shows this variant is a missense change (D777N) not predicted to cause loss of function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS1 is: "Strong Use PALB2 PS1 Splicing table Modification Type: General recommendation." The evidence shows no previously established pathogenic variant results in the same D777N amino acid change. 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." There is no de novo data available for this variant. 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 show a deleterious effect on the gene or gene product." No functional assays have been performed for PALB2 D777N. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PS4 is: "Strong Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5)." No case-control data are 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 without benign variation." D777N does not lie in a recognized PALB2 hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 (Supporting) is: "Variant absent in gnomAD or present in ≤1/300,000 alleles." The variant MAF=0.00159% (4/251,432), which exceeds 1/300,000 (0.00033%). Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Use Fanconi Anemia PM3 tables (Strong/Moderate/Supporting)." No evidence of the variant in trans with another pathogenic PALB2 variant exists. 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 deletions/insertions in a non‐repeat region or stop‐loss variants." This is a missense variant without 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 Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183." This is a missense variant. 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." No such data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "LOD ≥0.3 for Supporting, ≥0.6 for Moderate, ≥1.26 for Strong based on segregation evidence." No familial 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 with a low rate of benign missense variation and where missense variants are a common mechanism of disease." PALB2 pathogenicity is driven primarily by loss‐of‐function, and missense variants are not established as a common mechanism. 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." In silico splicing prediction (SpliceAI) shows no impact. 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." No phenotype or clinical data are 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 without available evidence." ClinVar submissions are conflicting (Likely benign and VUS) and this rule is discouraged. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BA1 (Stand Alone) is: "GnomAD Filtering Allele Frequency >0.1%." The variant MAF=0.00159% is below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 (Strong) is: "GnomAD Filtering Allele Frequency >0.01%." The variant MAF=0.00159% is below 0.01%. Therefore, this criterion is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Per Fanconi Anemia BS2 tables (Strong/Moderate/Supporting)." No observations in healthy adults have been reported. 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 deleterious effect." No functional data exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "LOD ≤-1.28 for Strong, ≤-0.64 for Moderate, ≤-0.32 for Supporting based on non‐segregation." No non‐segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 (Supporting) is: "Apply to all missense variants." D777N is a missense variant. Therefore, this criterion is applied at Supporting strength.
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 disorder." No such data exist. 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." This is a missense variant. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 (Supporting) is: "RNA: At least one well‐established in silico predictor (e.g. SpliceAI) shows no impact on splicing." SpliceAI predicts no splice impact (max score 0.01). 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." No such case information is available. 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 without available evidence." ClinVar submissions are conflicting and this rule is discouraged. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous and deep intronic variants with no predicted impact on splicing." This is a missense variant. Therefore, this criterion is not applied.