NM_024675.4:c.1058A>T

PALB2 · NP_078951.2:p.(Lys353Ile) · NM_024675.4

GRCh37: chr16:23646809 T>A · GRCh38: chr16:23635488 T>A

Gene: PALB2 Transcript: NM_024675.4

Final call

BP1 supporting PM2 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Lys353Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.1058A>T (p.Lys353Ile) variant has been reported in ClinVar as uncertain significance by a single submitter.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, and its gnomAD v4.1 allele frequency is therefore below the PALB2 PM2_Supporting threshold of 0.000333%.

PALB2-specific rules support BP1 for this missense variant, while SpliceAI predicts no significant splice impact with a maximum delta score of 0.00 and PVS1, PP3, and BP4 are not applied in this missense setting.

Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.

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
BA1	Not met	This variant is absent from gnomAD v4.1, so the observed allele frequency is 0%, which is below the PALB2 BA1 threshold of >0.1%; BA1 is not met.	cspec gnomad_v4
BP1	Met	This variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism for this gene.	cspec
BP2	N/A	BP2 is not used in the PALB2 VCEP framework for this gene, so it is not applicable to this variant.	cspec
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region, and the PALB2 VCEP does not use BP3 for PALB2.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, but the PALB2 VCEP does not apply BP4 to missense variants; BP4 is therefore not applicable here.	cspec spliceai
BP5	N/A	BP5 is not applicable because the PALB2 VCEP does not use this criterion for PALB2-related disease.	cspec
BP6	N/A	BP6 is not used in this VCEP framework, so it is not applicable to this variant.	cspec
BP7	N/A	BP7 is intended for synonymous or qualifying intronic variants, whereas this variant is a missense substitution; BP7 is therefore not applicable.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1, so the observed allele frequency is 0%, which is below the PALB2 BS1 threshold of >0.01%; BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing this variant in unaffected individuals under the PALB2 BS2 point-based framework, so BS2 cannot be assessed.	cspec
BS3	N/A	BS3 is not applicable in the PALB2 VCEP framework for this variant type, and no qualifying benign functional study evidence was identified for separate use.	cspec
BS4	Not assessed	No segregation study data or quantitative LOD/Bayes factor evidence were identified to show lack of segregation with disease, so BS4 cannot be assessed.	cspec
PM1	N/A	PM1 is not applicable because the PALB2 VCEP does not use PM1 for PALB2 missense variants.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed gnomAD v4.1 allele frequency is 0%, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%, so PM2_Supporting is met.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic PALB2 variant in an affected individual with Fanconi anemia, so PM3 cannot be assessed.	cspec
PM4	N/A	PM4 is not applicable because this variant is not a stop-loss variant, and the PALB2 VCEP does not use PM4 for missense variants.	cspec
PM5	N/A	PM5 is not applicable because the PALB2 VCEP does not use PM5 for missense changes; in PALB2 it is reserved for qualifying truncating or splice variants upstream of p.Tyr1183.	cspec
PM6	N/A	PM6 is not applicable because the PALB2 VCEP does not use de novo evidence under PM6 for PALB2-related disease.	cspec
PP1	Not assessed	No family segregation data or quantitative LOD/Bayes factor evidence were identified to show co-segregation with disease, so PP1 cannot be assessed.	cspec
PP2	N/A	PP2 is not applicable because the PALB2 VCEP does not use PP2 for PALB2 missense variants.	cspec
PP3	N/A	SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, and the PALB2 VCEP does not apply PP3 to missense variants; PP3 is therefore not applicable here.	cspec spliceai
PP4	N/A	PP4 is not applicable because the PALB2 VCEP does not use phenotype specificity under PP4 for PALB2-related disease in this setting.	cspec
PP5	N/A	PP5 is not used in this VCEP framework, so it is not applicable to this variant.	cspec
PS1	N/A	PS1 is not applicable because the PALB2 VCEP does not use PS1 for missense changes, and no splice-based PS1 evidence was identified for this variant.	cspec spliceai
PS2	N/A	PS2 is not applicable because the PALB2 VCEP does not use de novo evidence under PS2 for PALB2-related disease.	cspec
PS3	N/A	PS3 is not applicable in the PALB2 VCEP framework for this variant type, and no qualifying pathogenic functional study evidence was identified for separate use.	cspec
PS4	Not assessed	This variant has been reported in ClinVar as uncertain significance by a single submitter, but no case-control study data, odds ratio, relative risk, or qualifying statistical enrichment data were identified; PS4 cannot be assessed.	cspec clinvar
PVS1	N/A	This variant is a missense substitution and is not a nonsense, frameshift, or canonical ±1,2 splice variant. SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and the PALB2/generic PVS1 scaffold does not support PVS1 for this variant class; PVS1 is not applicable.	cspec pvs1_gene_context pvs1_variant_assessment spliceai

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