NM_024675.3:c.49-2A>T

PALB2 · NP_078951.2:p.? · NM_024675.3

GRCh37: chr16:23649452 T>A · GRCh38: chr16:23638131 T>A

Gene: PALB2 Transcript: NM_024675.3

Final call

VUS

PM2 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 NM_024675.3:c.49-2A>T (NP_078951.2:p.?) variant has been reported in ClinVar, where submissions include likely pathogenic and uncertain significance interpretations, and the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel has classified it as uncertain significance.

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,613,414 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of 0.000333% and well below the BS1 and BA1 population thresholds.

This variant affects a canonical splice acceptor position in a gene for which loss of function is an established disease mechanism, but the exact transcript consequence for this variant remains unresolved in the available evidence.

Available computational evidence is mixed: SpliceAI shows a max delta score of 0.00, whereas BayesDel is 0.63, and these data do not independently resolve the splice consequence for this canonical splice-site variant.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Not assessed	This variant affects the canonical -2 splice acceptor position in PALB2, and loss of function is an established disease mechanism for this gene. However, the available materials do not include the PALB2 exon-specific PVS1 decision-tree outcome or direct RNA evidence for this exact variant, and SpliceAI shows a max delta score of 0.00, so PVS1 is left for manual review rather than applied automatically.	cspec pvs1_gene_context pvs1_variant_assessment spliceai clinvar
PS1	Not assessed	The PALB2 specification indicates that PS1 for splice variants requires the PALB2 PS1 splicing table. No table-based match or equivalent previously established splice event was identified for this variant.	cspec
PS2	N/A	De novo evidence is not used for PALB2 in this specification.	cspec
PS3	N/A	PS3 is not applicable for PALB2 in this specification. No well-established functional study for this exact variant was provided that would override the panel rule.	cspec
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study or other enrichment analysis was identified showing a statistically significant excess in affected individuals. The available evidence does not establish the PALB2 PS4 threshold.	cspec clinvar
PM1	N/A	PM1 is not applicable for PALB2 because missense pathogenic variation has not been established as a disease mechanism in this specification, and this is not a mutational hot-spot criterion for the current variant type.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,613,414 alleles (AF 0.00006%), which is below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%). This supports PM2 at supporting strength.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assigned.	cspec
PM4	N/A	PM4 is not applicable for PALB2 except for stop-loss variants, and this variant is a splice-site change.	cspec
PM5	Not assessed	The PALB2 specification allows PM5_Supporting for selected truncating or splice variants only when the required RNA-based and NMD-prone conditions are met. Those variant-specific prerequisites were not established here.	cspec
PM6	N/A	PM6 is not used for PALB2 in this specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so the PALB2 PP1 thresholds were not met.	cspec clinvar
PP2	N/A	PP2 is not applicable for PALB2 in this specification.	cspec
PP3	N/A	For PALB2, PP3 for splicing is limited to silent, missense, in-frame, and intronic variants outside the donor and acceptor ±1,2 positions. This variant is a canonical -2 splice-site change, so PP3 is not applied.	cspec spliceai pvs1_variant_assessment
PP4	N/A	PP4 is not applicable for PALB2-related autosomal dominant cancer predisposition in this specification.	cspec
PP5	N/A	PP5 is not applicable and is not used for variant interpretation in this specification.	cspec
BA1	Not met	The highest observed population frequency for this variant in gnomAD v4.1 is 0.00008% in the European non-Finnish population, which is below the PALB2 BA1 threshold of >0.1%. BA1 is not met.	cspec gnomad_v4
BS1	Not met	The highest observed population frequency for this variant in gnomAD v4.1 is 0.00008% in the European non-Finnish population, which is below the PALB2 BS1 threshold of >0.01%. BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No qualifying observations in healthy individuals were identified that would allow PALB2 BS2 point assignment.	cspec
BS3	N/A	BS3 is not applicable for PALB2 in this specification, and no well-established study showing a normal effect for this exact variant was provided.	cspec
BS4	Not assessed	No non-segregation evidence was identified for this variant, so the PALB2 BS4 thresholds were not met.	cspec clinvar
BP1	N/A	BP1 applies to missense variants in PALB2. This variant is a splice-site change, so BP1 is not applicable.	cspec
BP2	N/A	BP2 is not applicable for PALB2 in this specification.	cspec
BP3	N/A	BP3 is not applicable for PALB2 in this specification.	cspec
BP4	Not assessed	SpliceAI shows no predicted splice impact for this variant (max delta score 0.00), which meets the PALB2 BP4 numeric threshold of ≤0.1. However, this is a canonical -2 splice acceptor variant that is primarily evaluated under the PALB2 PVS1 framework, and the available evidence does not establish that BP4 should be used to counter a canonical splice-site interpretation here.	cspec spliceai pvs1_variant_assessment
BP5	N/A	BP5 is not applicable for PALB2 in this specification.	cspec
BP6	N/A	BP6 is not applicable and is not used for PALB2 variant interpretation in this specification.	cspec
BP7	N/A	BP7 is intended for synonymous and deep intronic variants or for RNA evidence showing no aberrant splicing. This canonical -2 splice-site variant does not meet that use case, and no RNA study showing a normal splice outcome was identified.	cspec

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