PALB2 c.721A>G, p.Asn241Asp
NM_024675.4:c.721A>G
COSMIC ID: COSM9497078
Variant of Uncertain Significance (VUS)
Classified as Likely Benign based on strong population frequency evidence (BS1) exceeding the VCEP threshold, supported by benign clinical assertions (BP6) and the nonspecific nature of a missense change in PALB2 (BP1). No pathogenic criteria were met.
ACMG/AMP Criteria Applied
BS1
BP1
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.721A>G
Protein Change
N241D
Location
Exon 4
(Exon 4 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
No evidence of other pathogenic variants at position 241 in gene PALB2
Alternate Identifiers
COSM9497078
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.721A>G
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Clinical Data
Global Frequency
0.0616%
Common
Highest in Population
African/African American
0.653%
Common
Global: 0.0616%
African/African American: 0.653%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282556Alt: 174Homozygotes: 2
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.0616%, 174/282556 alleles, homozygotes = 2) and at a higher frequency in the African/African American population (MAF= 0.653%, 162/24820 alleles, homozygotes = 2). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
5 publications
Likely Benign
Based on 17 submitter reviews in ClinVar
Submitter Breakdown
8 LB
9 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (5)
Variant summary: The PALB2 c.721A>G (p.Asn241Asp) variant involves the alteration of a non-conserved nucleotide and 5/5 in silico tools predict a benign outcome for this variant, although these predictions have yet to be functionally assessed. This variant was found in 75/121762 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.006935 (71/10238). This frequency is about 44 times the estimated maximal expected allele frequency of a pathogenic PALB2 variant (0.0001563), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. Multiple publications have cited the variant in affected individuals, predominantly of African decent, although with limited information (ie, lack of co-occurrence and cosegregation data). In addition, multiple clinical diagnostic laboratories classified this variant as likely benign/benign. Taken together, this variant is classified as benign.
This alteration is classified as 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.
Curators: Marc Tischkowitz, Arleen D. Auerbach. Submitters to LOVD: Marc Tischkowitz, Melissa DeRycke, Yukihide Momozawa.
This variant is considered benign. Homozygosity for this variant has been confirmed in one or more individuals lacking clinical features consistent with gene-specific recessive disease, indicating that this variant is unlikely to be pathogenic. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Clinical Statement
This variant has been reported in ClinVar as Benign (9 clinical laboratories) and as Likely benign (8 clinical laboratories) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen expert panel.
Expert Panel Reviews
Benign
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen
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 241 in gene PALB2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.69polyphen_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 Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows: it is a missense change (N241D), not a null variant. 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 for this variant shows: no previously established pathogenic variant results in the same 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". The evidence for this variant shows: no confirmed de novo occurrence. Therefore, this criterion is not applied.
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". 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 Case-control studies; p-value ≤ .05 AND (Odds ratio … ≥3 or lower 95% CI ≥1.5)". The evidence for this variant shows: no case-control data. 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 functional domain without benign variation". The evidence for this variant shows: no data placing N241D in a known hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM2 is: "Supporting Variant absent in gnomAD or present in ≤ 1/300,000 alleles Modification Type: Gene-specific,Strength". The evidence for this variant shows: MAF = 0.0616% (~1/1,622 alleles), above the ≤1/300,000 threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM3 is: "Strong Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". The evidence for this variant shows: no evidence of trans observations in recessive disease. 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 stop-loss variants". The evidence for this variant shows: it is a missense substitution with no change in protein length. 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". The evidence for this variant shows: it is missense, not a truncating 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". The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting LOD ≥0.3 or Bayes Factor ≥2:1 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data. 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 low rate of benign missense variation and where pathogenic missense variants are common". The evidence for this variant shows: PALB2 tolerates missense and has both benign and pathogenic missense reported; no clear enrichment. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Protein: Do not use. RNA: At least one well-established in silico predictor shows impact on splicing". The evidence for this variant shows: mixed in silico predictions and no clear splice 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 highly specific for gene". The evidence for this variant shows: no phenotype or family history data. 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". The evidence for this variant shows: ClinVar reports it as benign/likely benign. 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% Modification Type: Disease-specific,Gene-specific". The evidence for this variant shows: MAF = 0.0616%, below the 0.1% threshold. Therefore, this criterion is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, the rule for BS1 is: "Strong GnomAD Filtering Allele Frequency greater than expected for disease >0.01% Modification Type: Disease-specific,Gene-specific". The evidence for this variant shows: MAF = 0.0616%, which is above 0.01%. Therefore, this criterion is applied at Strong strength because the allele frequency exceeds the gene-specific threshold for a benign classification.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS2 is: "Strong Per Fanconi Anemia BS2 tables Modification Type: Disease-specific". The evidence for this variant shows: no observation in healthy adults. 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". 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 Modification Type: Gene-specific". The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to VCEP guidelines, the rule for BP1 is: "Supporting Apply to all missense variants. Modification Type: Gene-specific". The evidence for this variant shows: N241D is a missense change. Therefore, this criterion is applied at Supporting strength because it is a missense variant 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". The evidence for this variant shows: no trans observations. 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: not an in-frame indel. Therefore, this criterion is not applied.
BP4
BP4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP4 is: "Supporting RNA: At least one well-established in silico predictor shows no impact on splicing; Protein: do not use". The evidence for this variant shows: mixed computational predictions and no consistent splice result. Therefore, this criterion is not applied.
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 data. 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". The evidence for this variant shows: ClinVar submissions classify it as benign or likely benign by multiple reputable laboratories. Therefore, this criterion is applied at Supporting strength because of the consensus benign reports.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Strong BP7_Strong(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants". The evidence for this variant shows: it is not silent or intronic. Therefore, this criterion is not applied.