PALB2 c.1882_1890del, p.Lys628_Cys630del
NM_024675.4:c.1882_1890del
COSMIC ID: COSM9277110
Variant of Uncertain Significance (VUS)
The in-frame deletion K628_C630del in PALB2 applies PM4 (Moderate) for protein length change and BP4 (Supporting) for lack of splicing impact. No other criteria are met due to absence of functional, segregation, or robust population evidence. The conflicting Moderate and Supporting criteria result in a classification of Variant of Uncertain Significance (VUS).
ACMG/AMP Criteria Applied
PM4
BP4
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.1882_1890del
Protein Change
K628_C630del
Location
Exon 5
(Exon 5 of 13)
5'Exon Structure (13 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSM9277110
Variant interpretation based on transcript NM_024675.4
Genome Browser
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HGVS InputNM_024675:c.1882_1890del
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
0.00319%
Rare
Highest in Population
Remaining individuals
0.0164%
Low Frequency
Global: 0.00319%
Remaining individuals: 0.0164%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250874Alt: 8Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is present in gnomAD (MAF= 0.00319%, 8/250874 alleles, homozygotes = 0) and at a higher frequency in the Remaining individuals population (MAF= 0.0164%, 1/6102 alleles, homozygotes = 0). The variant is rare (MAF < 0.1%), supporting PM2 criterion application.
Classification
7 publications
Uncertain Significance (VUS)
Based on 10 submitter reviews in ClinVar
Submitter Breakdown
9 VUS
1 LB
Pathogenic
Likely Path.
VUS
Likely Benign
Benign
Publications (7)
This variant is considered likely benign. 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].
Variant summary: PALB2 c.1882_1890delAAGTCCTGC (p.Lys628_Cys630del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 3.2e-05 in 250874 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1882_1890delAAGTCCTGC has been reported in the literature in individuals affected gastric cancer (example: Sahasrabudhe_2017). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
The c.1882_1890delAAGTCCTGC variant (also known as p.K628_C630del) is located in coding exon 5 of the PALB2 gene. This variant results from an in-frame AAGTCCTGC deletion at nucleotide positions 1882 to 1890. This results in the in-frame deletion of 3 amino acid residues at codons 628 to 630. This alteration has been reported in at least one breast cancer patient in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This alteration was also identified in two individuals diagnosed with gastric cancer (Sahasrabudhe R et al. Gastroenterology 2017 Apr;152(5):983-986.e6). This region is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). Based on the available evidence, the clinical significance of this alteration remains unclear.
Clinical Statement
This variant has been reported in ClinVar as Uncertain significance (9 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
Functional Summary
The PALB2 K628_C630del variant has not been functionally characterized, and its biological significance remains unknown.
Database Previews
OncoKB
JAX-CKB
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Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Mixed/VUS
PP3 Applied
No
Additional Predictors
Benign:
CADD: 1.45
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 an in-frame deletion (K628_C630del) that does not result in a null effect or loss-of-function. Therefore, this criterion is not applied because the variant does not meet the definition of a null variant in PALB2.
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 yielding 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". There is no information on de novo occurrence or parental testing. Therefore, this criterion is not applied.
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". There are no functional studies on this variant. 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, hazard ratio, or relative risk ≥3 OR lower 95% CI ≥1.5)". No case-control or cohort data are available. 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 and well-established functional domain without benign variation". There is no evidence that K628_C630del lies 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". The evidence shows MAF = 0.00319% (~8/250,874 alleles), which exceeds 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: "Use Fanconi Anemia PM3 tables". No trans or compound heterozygous data are available. Therefore, this criterion is not applied.
PM4
PM4 (Moderate)
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions in a non-repeat region or stop-loss variants". The evidence shows an in-frame deletion of three amino acids (K628_C630del) not in a repetitive region. Therefore, this criterion is applied at Moderate strength.
PM5
PM5 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PM5 is: "Supporting Strength: Apply to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183". This variant is an in-frame deletion, not a frameshifting or truncating change. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "De novo (without confirmation of paternity) in a patient with the disease and no family history". There is no de novo information. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP1 is: "Supporting/Moderate/Strong Strength based on segregation LOD scores". 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 a low rate of benign missense variation". This variant is an in-frame deletion, not a missense change. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for PP3 is: "Supporting Strength: Protein: Do not use. RNA: At least one well-established in silico predictor shows impact on splicing". SpliceAI predicts no impact on splicing (max score 0.06). 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 is highly specific for a disease with a single genetic etiology". No phenotype or family history data are 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 submissions are predominantly VUS or 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%". The variant MAF = 0.00319% is below 0.1%. Therefore, this criterion is not applied.
BS1
BS1 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS1 is: "Strong Strength: GnomAD Filtering Allele Frequency greater than expected for disease >0.01%". The variant MAF = 0.00319% is below 0.01%. 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 healthy adult observation data are available. 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 on protein function". No functional studies are available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BS4 is: "Strong/Moderate/Supporting Strength based on negative segregation LOD scores". 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: "Supporting Strength: Apply to all missense variants". This variant is an in-frame deletion, not missense. 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 recessive disorder or in cis with a pathogenic variant for any disorder". No such observations are reported. 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". There is no evidence this deletion lies in a repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to VCEP guidelines, the rule for BP4 is: "Supporting Strength: RNA: At least one well-established in silico predictor (e.g. SpliceAI) shows no impact on splicing". SpliceAI predicts minimal impact (max score 0.06). 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 alternate molecular findings are reported. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign". ClinVar consensus is uncertain or likely benign but not definitive. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to VCEP guidelines, the rule for BP7 is: "Strong/Moderate/Supporting Strength for lack of RNA defect in synonymous or intronic variants". This is a coding in-frame deletion, not synonymous or intronic. Therefore, this criterion is not applied.