PALB2 c.2273C>G, p.Pro758Arg
NM_024675.4:c.2273C>G
Likely Benign
This PALB2 P758R variant is classified as Likely Benign based on three supporting benign criteria (BP1, BP4, BP6) per PALB2 VCEP and ACMG guidelines, with no evidence supporting pathogenic criteria.
ACMG/AMP Criteria Applied
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.2273C>G
Protein Change
P758R
Location
Exon 5
(Exon 5 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
ClinVar reports other pathogenic variants at position 758: P758L
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.2273C>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000707%
Very Rare
Highest in Population
East Asian
0.01%
Low Frequency
Global: 0.000707%
East Asian: 0.01%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282892Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000707%, 2/282892 alleles, homozygotes = 0) and at a higher frequency in the East Asian population (MAF= 0.01%, 2/19952 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
Likely Benign
Based on 1 submitter review in ClinVar
Submitter Breakdown
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (0)
No publication details.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (1 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
ClinVar reports other pathogenic variants at position 758: P758L
PM5 criterion applied.
Computational Analysis
Pathogenicity Predictions
REVEL Score
0.146
0.146
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 2.67metasvm: 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 for this variant shows: it is a missense change (P758R) and does not introduce a null allele. Therefore, this criterion is not applied at Not Applied strength because the variant does not meet the null variant requirement.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PS1 is: "Use PALB2 PS1 Splicing table Modification Type: General recommendation." The evidence for this variant shows: no identical amino acid change via a different nucleotide and no splicing alteration. Therefore, this criterion is not applied at Not Applied strength.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PS2 is: "Confirmed de novo (both maternity and paternity confirmed)." The evidence for this variant shows: no de novo occurrence has been documented. Therefore, this criterion is not applied at Not Applied strength.
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 studies exist for P758R. Therefore, this criterion is not applied at Not Applied strength.
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 or segregation statistics are available. Therefore, this criterion is not applied at Not Applied strength.
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 known mutational hotspot or critical PALB2 domain at residue 758. Therefore, this criterion is not applied at Not Applied strength.
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 evidence for this variant shows: it is present at 2/282,892 alleles (~1/141,000) in gnomAD, exceeding the VCEP threshold. Therefore, this criterion is not applied at Not Applied strength.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM3 is: "Use Fanconi Anemia PM3 tables." The evidence for this variant shows: no observations in trans with a pathogenic PALB2 variant. Therefore, this criterion is not applied at Not Applied strength.
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 or stop-loss." The evidence for this variant shows: it is a single amino acid substitution without length change. Therefore, this criterion is not applied at Not Applied strength.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PM5 (Supporting) is: "Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183." The evidence for this variant shows: it is a missense change, not a truncating or frameshift. Therefore, this criterion is not applied at Not Applied strength.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PM6 is: "Assumed de novo, without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data reported. Therefore, this criterion is not applied at Not Applied strength.
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." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied at Not Applied strength.
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 missense is a common mechanism." The evidence for this variant shows: insufficient data on PALB2 missense constraint. Therefore, this criterion is not applied at Not Applied strength.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for PP3 is: "Supporting: Protein: do not use. RNA: at least one in silico predictor shows splicing impact." The evidence for this variant shows: SpliceAI score of 0.01 indicates no splicing impact. Therefore, this criterion is not applied at Not Applied strength.
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 phenotype data provided. Therefore, this criterion is not applied at Not Applied strength.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for PP5 is: "Reputable source reports variant as pathogenic but no evidence is available." The evidence for this variant shows: ClinVar reports it as likely benign. Therefore, this criterion is not applied at Not Applied strength.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BA1 is: "GnomAD Filtering Allele Frequency >0.1%." The evidence for this variant shows: allele frequency ~0.0007%, below the threshold. Therefore, this criterion is not applied at Not Applied strength.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS1 is: "GnomAD Filtering Allele Frequency >0.01%." The evidence for this variant shows: allele frequency ~0.0007%, below the threshold. Therefore, this criterion is not applied at Not Applied strength.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS2 is: "Use Fanconi Anemia BS2 tables." The evidence for this variant shows: no observations in healthy controls with appropriate phenotyping. Therefore, this criterion is not applied at Not Applied strength.
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 exist. Therefore, this criterion is not applied at Not Applied strength.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines: the rule for BS4 is: "LOD ≤ -1.28 or LR ≤0.053:1 for lack of segregation." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied at Not Applied strength.
BP1
BP1 (Supporting)
According to VCEP guidelines: the rule for BP1 is: "Supporting: Apply to all missense variants." The evidence for this variant shows: it is a missense change (P758R). Therefore, this criterion is applied at Supporting strength because missense is not the established mechanism for PALB2 disease.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BP2 is: "Observed in trans with a pathogenic variant in a fully penetrant gene/disease." The evidence for this variant shows: no trans observations. Therefore, this criterion is not applied at Not Applied strength.
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 known function." The evidence for this variant shows: it is a missense SNV. Therefore, this criterion is not applied at Not Applied strength.
BP4
BP4 (Supporting)
According to VCEP guidelines: the rule for BP4 is: "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 maximum score 0.01, indicating minimal splicing effect. Therefore, this criterion is applied at Supporting strength because no splicing impact is predicted.
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 at Not Applied strength.
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 it as Likely Benign from one clinical laboratory. Therefore, this criterion is applied at Supporting strength because a reputable source lists it as benign without underlying data.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines: the rule for BP7 is: "Synonymous variant with no predicted splice impact and no conserved splice motif." The evidence for this variant shows: it is a missense change. Therefore, this criterion is not applied at Not Applied strength.