PALB2 c.721A>G, p.Asn241Asp
NM_024675.4:c.721A>G
COSMIC ID: COSM9497078
Likely Benign
The PALB2 N241D variant is observed at a frequency (0.0616%) exceeding the threshold for pathogenicity, lacks evidence of functional impact or disease segregation, is predicted to have no splicing effect, and is reported as benign by expert panels; collectively, strong (BS1) and supporting (BP1, BP4, BP6) benign criteria lead to a Likely Benign classification.
ACMG/AMP Criteria Applied
BS1
BP1
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.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
Active Tracks
ConservationRefSeqClinVargnomAD
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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 PVS1 decision tree specifies PVS1 applies to predicted loss-of-function variants in PALB2; the rule for PVS1 is: "Use PALB2 PVS1 Decision Tree Modification Type: Gene-specific,Strength". The evidence for this variant shows a missense change (N241D) rather than a loss-of-function. Therefore, this criterion is not applied.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 applies when a variant results in the same amino acid change as a known pathogenic variant; the rule is: "Use PALB2 PS1 Splicing table Modification Type: General recommendation". The evidence for this variant shows a novel N241D missense change with no prior pathogenic N241D reported. Therefore, this criterion is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 applies for confirmed de novo occurrence; the rule is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history". No de novo data are available for this variant. Therefore, this criterion is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 applies when well-established functional studies show a deleterious effect; the rule is: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product". No functional studies have been performed for PALB2 N241D. Therefore, this criterion is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 requires strong case-control evidence for association with disease; the rule is: "Case-control studies; p-value ≤.05 AND (Odds ratio ≥3 OR lower 95% CI ≥1.5)". No such studies exist for this variant. Therefore, this criterion is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hotspots or critical functional domains without benign variation; the rule is: "Located in a mutational hot spot and/or critical and well-established functional domain". N241D is not in a known hotspot or critical domain. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2_Supporting applies if a variant is absent in gnomAD or present in ≤1/300,000 alleles; the rule is: "Supporting: Variant absent in gnomAD or present in ≤1/300,000 alleles". The evidence for this variant shows a gnomAD frequency of 0.0616% (174/282,556), which exceeds the threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies to recessive disorders with observed in trans occurrences; the rule is: "Use Fanconi Anemia PM3 tables Modification Type: Disease-specific,Strength". PALB2 N241D has no reported trans observations in Fanconi anemia. Therefore, this criterion 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 variants; the rule is: "Protein length changes as a result of in-frame deletions/insertions in a non-repeat region or stop-loss variants". N241D is a missense SNV. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to truncating variants upstream of p.Tyr1183 in PALB2; the rule is: "Supporting: Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183". N241D is a missense variant. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to presumed de novo without confirmation; the rule is: "Assumed de novo, but without confirmation of paternity and maternity". No de novo data are available. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 applies for segregation evidence in PALB2; the rule is: "Supporting: LOD ≥0.3 or Bayes Factor ≥2:1". No segregation data exist for N241D. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies when a missense variant occurs in a gene with low rate of benign missense; the rule is: "Missense variant in a gene with a low rate of benign missense variants and where missense is a common mechanism of disease". PALB2 has known pathogenic missense, so this rule is not met. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 for RNA applies when at least one in silico predictor shows impact on splicing; the rule is: "Supporting: At least one well-established in silico predictor shows impact on splicing". SpliceAI score is 0.01 indicating no splicing impact. Therefore, this criterion is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies when patient phenotype is highly specific for a disease with a single genetic etiology; the rule is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic cause". No phenotype data are provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies for reputable sources reporting pathogenic without evidence; the rule is: "Reputable source reports variant as pathogenic but evidence is unavailable". This variant is reported as benign by expert panels, not pathogenic. Therefore, this criterion is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 applies at stand-alone strength for allele frequency >0.1% in gnomAD; the rule is: "Stand Alone: GnomAD Filtering Allele Frequency >0.1%". The allele frequency is 0.0616%, which is below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Strong)
According to VCEP guidelines, BS1 applies when gnomAD filtering allele frequency is greater than expected for disease (>0.01%); the rule is: "Strong: GnomAD Filtering Allele Frequency greater than expected for disease >.01%". The evidence for this variant shows a gnomAD frequency of 0.0616%, which exceeds 0.01%. Therefore, this criterion is applied at Strong strength because the population frequency is higher than expected for pathogenic PALB2 variants.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies per Fanconi Anemia tables for observations in healthy adults; the rule is: "Per Fanconi Anemia BS2 tables". No such observations are reported. Therefore, this criterion is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 applies when well-established functional studies show no damaging effect; the rule is: "Well-established functional studies show no harmful effect on protein function". No functional data are available for N241D. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 applies for lack of segregation; the rule is: "Strong: LOD ≤-1.28 or Bayes Factor ≤0.053:1". No segregation data exist. Therefore, this criterion is not applied.
BP1
BP1 (Supporting)
According to VCEP guidelines, BP1 applies to all missense variants in PALB2; the rule is: "Supporting: Apply to all missense variants". The evidence for this variant shows a missense substitution (N241D). 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, BP2 applies when observed in trans with a pathogenic variant for a recessive disorder; the rule is: "Observed in trans with a pathogenic variant for a fully penetrant dominant gene or recessive disorder". There are no trans observations with a pathogenic PALB2 variant. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions; the rule is: "In-frame indels in a repetitive region without a known function". This is a missense SNV. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4 applies for RNA splicing predictions showing no impact; the rule is: "Supporting: RNA: At least one well-established in silico predictor (e.g., SpliceAI) shows no impact on splicing". The evidence shows a SpliceAI score of 0.01 indicating no splicing effect. Therefore, this criterion is applied at Supporting strength because in silico tools predict no impact on splicing.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when a variant is found in a case with an alternate molecular basis for disease; the rule is: "Variant found in a case with an alternate molecular basis for disease". No such case is reported. Therefore, this criterion is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign without available evidence; the rule is: "Reputable source reports variant as benign but evidence not available". The evidence shows ClinVar entries by multiple expert panels reporting N241D as benign. Therefore, this criterion is applied at Supporting strength because of consensus benign assertions without accessible underlying data.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or intronic variants with no impact on splicing and no conservation; the rule is: "Supporting: Observed lack of aberrant RNA defect for silent substitutions and intronic variants". N241D is a missense variant. Therefore, this criterion is not applied.