PALB2 c.902A>G, p.Asp301Gly
NM_024675.4:c.902A>G
Variant of Uncertain Significance (VUS)
The variant NM_024675.4:c.902A>G (p.D301G) is a rare PALB2 missense change with no functional or segregation evidence for pathogenicity. Three benign supporting criteria (BP1, BP4, BP6) yield a Likely Benign classification.
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.902A>G
Protein Change
D301G
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 301 in gene PALB2
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.902A>G
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.000398%
Extremely Rare
Highest in Population
Admixed American
0.00289%
Rare
Global: 0.000398%
Admixed American: 0.00289%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 251324Alt: 1Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.000398%, 1/251324 alleles, homozygotes = 0) and at a higher frequency in the Admixed American population (MAF= 0.00289%, 1/34580 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
3 publications
Uncertain Significance (VUS)
Based on 8 submitter reviews in ClinVar
Submitter Breakdown
7 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (3)
In the published literature, this variant has been reported in individuals with breast cancer (PMIDs: 32885271 (2021), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/PALB2)) and healthy individuals (PMID: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/PALB2)). The frequency of this variant in the general population, 0.000004 (1/251324 chromosomes (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.
This alteration is classified as likely 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.
This missense variant replaces aspartic acid with glycine at codon 301 of the PALB2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been detected in a breast cancer case-control meta-analysis in 2/60463 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID PALB2_010729) and in an ovarian cancer case-control study in 0/6385 cases and 2/6115 unaffected individuals (PMID: 32546565). This variant has been identified in 1/251324 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and 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
No evidence of other pathogenic variants at position 301 in gene PALB2
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 0.35polyphen_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, PVS1 is evaluated using the PALB2 PVS1 Decision Tree: null (LOF) variants receive Very Strong evidence. The evidence for this variant is that NM_024675.4:c.902A>G (p.D301G) is a missense change, not predicted to result in loss of function. Therefore, this criterion is not applied because the variant does not create a null allele.
PS1
PS1 (Not Applied) Strength Modified
According to VCEP guidelines, PS1 is evaluated using the PALB2 PS1 Splicing table for amino acid–identical changes. The evidence for this variant is that D301G does not match the amino acid change of any previously established pathogenic variant. Therefore, PS1 is not applied.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS2 requires confirmed de novo occurrence (both maternity and paternity). There are no data on de novo status for this variant. Therefore, PS2 is not applied.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, PS3 requires well-established functional studies supportive of a damaging effect. No functional assays have been reported for PALB2 D301G. Therefore, PS3 is not applied.
PS4
PS4 (Not Applied) Strength Modified
According to VCEP guidelines, PS4 for PALB2 requires significant case-control data (p≤0.05 and OR≥3). No case-control or patient cohort data are available for this variant. Therefore, PS4 is not applied.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM1 applies to variants in mutational hot spots or critical functional domains. D301G is not located in a recognized PALB2 hotspot or characterized domain. Therefore, PM1 is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to VCEP guidelines, PM2_Supporting applies to variants absent from gnomAD or present in ≤1/300,000 alleles. This variant is present at 1/251,324 alleles in gnomAD (>1/300,000). Therefore, PM2 is not applied.
PM3
PM3 (Not Applied) Strength Modified
According to VCEP guidelines, PM3 applies in trans observation for recessive Fanconi anemia. No biallelic or trans data exist for this variant. Therefore, PM3 is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM4 applies to protein length changes (in-frame indels). This is a missense substitution with no length change. Therefore, PM4 is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, PM5 applies to novel stop or frameshift variants upstream of p.Tyr1183. D301G is a missense change. Therefore, PM5 is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, PM6 applies to assumed de novo variants without confirmation. No de novo information is available. Therefore, PM6 is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, PP1 requires segregation data with disease. No family segregation data are available for this variant. Therefore, PP1 is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP2 applies for a missense variant in a gene where such variants are a common mechanism of disease. PALB2 disease mechanism is loss of function, and missense variants are not established common drivers. Therefore, PP2 is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, PP3 (RNA) requires at least one in silico predictor showing an impact on splicing. SpliceAI predicts no splicing impact (score 0.02). Therefore, PP3 is not applied.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP4 applies when patient phenotype is highly specific for gene. No phenotype data are available. Therefore, PP4 is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, PP5 applies when a reputable source reports the variant as pathogenic. ClinVar reports this variant as VUS or Likely benign, not pathogenic. Therefore, PP5 is not applied.
BA1
BA1 (Not Applied) Strength Modified
According to VCEP guidelines, BA1 requires allele frequency >0.1% in gnomAD. This variant has MAF 0.000398% (<0.1%). Therefore, BA1 is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, BS1 requires allele frequency >0.01% for PALB2. This variant’s MAF is 0.000398% (<0.01%). Therefore, BS1 is not applied.
BS2
BS2 (Not Applied) Strength Modified
According to VCEP guidelines, BS2 applies when variant is observed in healthy adults per Fanconi anemia tables. No such data exist. Therefore, BS2 is not applied.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BS3 requires well-established functional studies showing no damaging effect. No functional data are available. Therefore, BS3 is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, BS4 requires non-segregation in families with LOD ≤–1.28. No segregation data exist. Therefore, BS4 is not applied.
BP1
BP1 (Supporting)
According to VCEP guidelines, BP1_Supporting applies to all missense variants in PALB2 (gene where LOF is disease mechanism). D301G is a missense variant. Therefore, BP1 is applied at Supporting strength.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP2 applies when variant is observed in trans with a pathogenic variant for a dominant disorder. No trans data are available. Therefore, BP2 is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP3 applies to in-frame indels in repetitive regions. This is a missense substitution. Therefore, BP3 is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, BP4_Supporting (RNA) requires at least one predictor showing no splicing impact. SpliceAI score 0.02 predicts no splicing effect. Therefore, BP4 is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, BP5 applies when variant is found in a case with an alternate molecular cause. No such information is available. Therefore, BP5 is not applied.
BP6
BP6 (Supporting)
According to standard ACMG guidelines, BP6 applies when a reputable source reports the variant as benign. ClinVar includes one Likely benign assertion. Therefore, BP6 is applied at Supporting strength.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, BP7 applies to synonymous or deep intronic variants with no RNA impact. This is a missense variant. Therefore, BP7 is not applied.