PALB2 c.1623G>A, p.Arg541=
NM_024675.4:c.1623G>A
Likely Benign
This synonymous variant has no predicted impact on splicing, is extremely rare in population databases, and is reported as benign in ClinVar. Only two Supporting benign criteria (BP4, BP6) apply, leading to a Likely Benign classification.
ACMG/AMP Criteria Applied
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.1623G>A
Protein Change
R541=
Location
Exon 4
(Exon 4 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.1623G>A
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00283%
Rare
Highest in Population
African/African American
0.012%
Low Frequency
Global: 0.00283%
African/African American: 0.012%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 282862Alt: 8Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00283%, 8/282862 alleles, homozygotes = 0) and at a higher frequency in the African/African American population (MAF= 0.012%, 3/24972 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Likely Benign
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
7 LB
3 B
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.
Clinical Statement
This variant has been reported in ClinVar as Likely benign (7 clinical laboratories) and as Benign (3 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
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: -0.28
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". The evidence for this variant shows it is a synonymous change with no predicted impact on splicing (SpliceAI score 0.03). Therefore, this criterion is not applied because the variant does not meet loss-of-function criteria.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a known pathogenic variant but by a different nucleotide change." The evidence for this variant shows it is synonymous (no amino acid change). Therefore, this criterion is not applied because there is no amino acid alteration.
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 or parental testing data available. Therefore, this criterion is not applied due to lack of de novo evidence.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product." No functional studies have been performed. Therefore, this criterion is not applied because functional evidence is missing.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "The prevalence of the variant in affected individuals is significantly increased compared with controls." No case-control or cohort data are available. Therefore, this criterion is not applied due to lack of case-control evidence.
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 variant is synonymous and not located in a known functional 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 evidence shows a gnomAD allele count of 8/282,862 (~1/35,000), which exceeds the ≤1/300,000 threshold. Therefore, this criterion is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "For recessive disorders, detected in trans with a pathogenic variant." No trans-phase or compound heterozygosity data are available. 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 or stop-loss variants." The variant is synonymous with no change in protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different missense change is pathogenic." The variant is synonymous. 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 de novo data are present. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Segregation evidence with LOD score thresholds." No 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 low rate of benign missense variation and where missense is a common mechanism of disease." The variant is synonymous. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 (protein predictors not used; RNA predictors used) is: "At least one well-established in silico predictor shows impact on splicing." SpliceAI predicts no splicing impact (score 0.03). Therefore, PP3 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 clinical phenotype or family history is 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." ClinVar reports this variant 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: "GnomAD Filtering Allele Frequency >0.1%." The maximum observed frequency is 0.012% in African/African American. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "GnomAD Filtering Allele Frequency >0.01%." The observed frequency is 0.00283%, below the 0.01% threshold. 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." No homozygotes or healthy adult observations are 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 damaging effect." No functional study data exist. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Segregation data with LOD ≤ -1.28." No segregation data are available. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP1 is: "Apply to all missense variants." The variant is synonymous. Therefore, this criterion is not applied.
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 dominant gene or in cis with another pathogenic variant without causing disease." No such data are available. 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 variant is synonymous. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing." SpliceAI predicts no splice impact (score 0.03). 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‐level data exist. 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." ClinVar entries (7 labs likely benign, 3 labs benign) support benign. Therefore, this criterion is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7_Strong(RNA) is: "Observed lack of aberrant RNA defect for silent substitutions." No RNA assay data exist, only predictive. Therefore, this criterion is not applied.