NM_024675.3:c.3113G>A

PALB2 · NP_078951.2:p.(Trp1038Ter) · NM_024675.3

GRCh37: chr16:23632683 C>T · GRCh38: chr16:23621362 C>T

Gene: PALB2 Transcript: NM_024675.3

Final call

Pathogenic

PVS1 very strong BS1 strong PM5 supporting PP5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Trp1038Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.3113G>A (p.Trp1038Ter) variant has been reported in ClinVar with a pathogenic expert panel classification and additional pathogenic clinical laboratory submissions.

This variant is present in gnomAD v4 at a total allele frequency of 0.020838% and reaches 0.027778% in the highest observed population, which is above the PALB2 BS1 threshold of 0.01% and above the PM2_Supporting threshold of 0.000333%.

This variant introduces a premature termination codon and is consistent with a loss-of-function effect in PALB2, a gene for which loss of function is an established disease mechanism in the PALB2 VCEP framework.

SpliceAI predicts splice impact with a maximum delta score of 0.74, but under PALB2-specific rules PP3 is not additionally applied for this nonsense variant type.

Final determination: Rule4 in the Richards et.al., 2015 - Combining rules v1.2.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Pathogenic.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	This variant is a nonsense change predicted to result in p.(Trp1038Ter)/p.(W1038*). In the PALB2 VCEP framework, loss of function is an established disease mechanism, and the premature termination event occurs well upstream of the final exon-exon junction, which is consistent with a loss-of-function effect and supports PVS1 at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment
PS4	Not assessed	This variant has been reported in ClinVar, including an expert panel pathogenic classification, but no reviewed case-control result meeting the PALB2 PS4 requirement of p-value <=0.05 with an odds ratio, hazard ratio, or relative risk >=3 or lower 95% confidence interval >=1.5 was identified here.	clinvar cspec
PP1	Not assessed	No quantitative co-segregation evidence meeting PALB2 PP1 thresholds was identified. Available evidence does not provide a LOD score, Bayes factor, or a documented number of informative segregations sufficient for PP1.	cspec clinvar
BS4	Not assessed	No quantitative non-segregation evidence meeting PALB2 BS4 thresholds was identified. Available evidence does not show a LOD score or Bayes factor supporting lack of segregation with disease.	cspec clinvar
PM2	Not met	This variant is present in gnomAD v4 at a total allele frequency of 0.0002083848 (0.020838%) with highest observed population frequency 0.0002777778 (0.027778%) and therefore is above the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%). PM2 is not met.	gnomad_v4 gnomad_v2 cspec
BS1	Met	This variant is present in gnomAD v4 with highest observed population allele frequency 0.0002777778 (0.027778%), which is above the PALB2 BS1 threshold of 0.01%. BS1 is met at strong strength.	gnomad_v4 cspec
BA1	Not met	This variant does not meet the PALB2 BA1 threshold. The highest observed population allele frequency in gnomAD v4 is 0.0002777778 (0.027778%), which is below the BA1 threshold of 0.1%.	gnomad_v4 cspec
PM5	Met	This truncating variant creates a premature termination codon at p.(Trp1038Ter), which is upstream of the PALB2 truncation cutoff p.Tyr1183 specified for PM5_Supporting. PM5 is met at supporting strength under the PALB2 VCEP rule.	cspec
PP3	N/A	SpliceAI predicts possible splice impact with a maximum delta score of 0.74, but the PALB2 PP3 rule is specified for silent, missense/in-frame, and relevant non-canonical intronic variants rather than this nonsense variant. PP3 is therefore not applied.	spliceai cspec
BP4	N/A	BP4 is not applicable because this is not a missense variant, and splicing prediction does not show a low-impact result. SpliceAI shows a maximum delta score of 0.74, which is above the PALB2 BP4 threshold of <=0.1.	spliceai cspec
PS1	Not assessed	PALB2 PS1 relies on a gene-specific splicing table. No reviewed evidence was identified showing that this variant has the same established splice consequence as another PALB2 variant already classified at the required strength.	cspec spliceai
PM3	Not assessed	No reviewed evidence was identified showing this variant in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, and no PM3 point total was available. PM3 is not currently assessed.	cspec clinvar
BS2	Not assessed	No reviewed evidence was identified showing this variant in healthy adults or in unaffected individuals meeting PALB2 BS2 point-based thresholds. Population database observations alone are not sufficient for BS2 in this framework.	cspec gnomad_v4
BP7	N/A	This is not a synonymous or deep intronic variant, so PALB2 BP7 does not apply.	cspec
BP1	N/A	This is not a missense variant. PALB2 BP1 applies to missense variants only.	cspec
PM1	N/A	PALB2 PM1 is not applicable in this framework. No hotspot-based rule applies for this variant.	cspec hotspots
PM4	N/A	PALB2 PM4 is reserved for stop-loss variants in this framework and does not apply to this nonsense variant.	cspec
PP4	N/A	PALB2 PP4 is not used for the autosomal dominant cancer-predisposition setting in this framework because the phenotype is not sufficiently specific.	cspec
PM6	N/A	PALB2 PM6 is not applicable in this framework.	cspec
BP2	N/A	PALB2 BP2 is not applicable in this framework.	cspec
PP2	N/A	PALB2 PP2 is not applicable in this framework.	cspec
PS3	N/A	PALB2 PS3 is not applicable in this framework for this variant assessment.	cspec oncokb
BS3	N/A	PALB2 BS3 is not applicable in this framework for this variant assessment.	cspec
BP3	N/A	PALB2 BP3 is not applicable in this framework.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
PS2	N/A	PALB2 PS2 is not applicable in this framework.	cspec
BP5	N/A	PALB2 BP5 is not applicable in this framework.	cspec
BP6	N/A	PALB2 BP6 is not applicable for this VCEP.	cspec

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