Variant classification summary

NM_024675.4:c.2863dupA

PALB2 · NP_078951.2:p.(Ser955LysfsTer2) · NM_024675.4

GRCh37: chr16:23634422 C>CT · GRCh38: chr16:23623101 C>CT

Gene: PALB2 Transcript: NM_024675.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Ser955LysfsTer2)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.2863dup (p.(Ser955LysfsTer2)) variant has not been observed in somatic cancers in COSMIC and is absent from ClinVar.

2

This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, placing the observed population frequency at 0%, below the PALB2 PM2_Supporting threshold of 0.000333% in gnomAD v4.

3

Published PALB2 studies and the expert-panel specification support loss of function as an established disease mechanism for PALB2-related cancer predisposition, and this duplication is predicted to cause an early truncating frameshift, p.(Ser955LysfsTer2).

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, supporting interpretation of the primary effect as a truncating frameshift rather than an alternative splice-driven event.

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 frameshift duplication predicted to create an early premature termination codon, p.(Ser955LysfsTer2), in PALB2. The PALB2 expert panel uses a gene-specific PVS1 framework, and loss of function is an established disease mechanism for PALB2-related cancer predisposition, supporting PVS1 at very strong strength for this truncating event.	cspec pvs1_gene_context pvs1_variant_assessment
PM2	Met	This variant is absent from gnomAD v4.1, absent from gnomAD v2.1, and absent from gnomAD-Canada. The observed population frequency is therefore 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1/300,000) in gnomAD v4.	cspec gnomad_v4 gnomad_v2 gnomad_canada
PM5	Met	The PALB2 expert panel repurposes PM5 for truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift variant, p.(Ser955LysfsTer2), is upstream of p.Tyr1183 and therefore meets PM5 at supporting strength under the PALB2-specific rule.	cspec pm5_candidates
BA1	Not met	This variant is absent from gnomAD v4.1. The observed population frequency is 0%, which is below the BA1 threshold of 0.1%, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1. The observed population frequency is 0%, which is below the BS1 threshold of 0.01%, so BS1 is not met.	cspec gnomad_v4
BP4	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the BP4 splicing threshold of 0.1. However, this benign splice prediction does not offset the independently damaging truncating frameshift effect, so BP4 is not applied.	cspec spliceai
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2. REVEL and BayesDel were not available for this indel, and the available computational evidence does not support PP3.	cspec spliceai
PS4	Not assessed	No variant-specific case-control data were identified showing a statistically increased prevalence of this variant in affected individuals compared with controls, so PS4 cannot currently be assessed.
PP1	Not assessed	No segregation data were identified that would allow calculation of a PALB2-specific LOD score or Bayes factor, so PP1 cannot currently be assessed.
BS4	Not assessed	No non-segregation data were identified that would allow calculation of a PALB2-specific LOD score or Bayes factor, so BS4 cannot currently be assessed.
PM3	Not assessed	No evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot currently be assessed.
BS2	Not assessed	No well-documented observations of this variant in unaffected individuals meeting the PALB2/Fanconi anemia BS2 framework were identified, so BS2 cannot currently be assessed.
PS1	N/A	This is a truncating frameshift variant, and the PALB2 PS1 specification is restricted to splice-based comparisons rather than truncating variants. PS1 is therefore not applicable.	cspec
BP1	N/A	This criterion applies to missense variants. Because this variant is a frameshift duplication rather than a missense change, BP1 is not applicable.	cspec
BP7	N/A	This criterion is intended for synonymous or deep intronic variants, or for RNA studies showing no aberrant splicing in those variant classes. Because this variant is a coding frameshift duplication, BP7 is not applicable.	cspec
PM4	N/A	The PALB2 expert panel does not use PM4 for frameshift variants and limits PM4 to stop-loss variants. PM4 is therefore not applicable.	cspec
BS3	N/A	The PALB2 expert panel does not apply BS3 for protein functional assays in this framework. BS3 is therefore not applicable.	cspec
PP4	N/A	The PALB2 expert panel does not use PP4 for the autosomal dominant cancer-predisposition setting because the phenotype is genetically heterogeneous. PP4 is not applicable.	cspec
PM6	N/A	The PALB2 expert panel does not use PM6 for this disorder framework. PM6 is not applicable.	cspec
PM1	N/A	The PALB2 expert panel does not use PM1 because missense pathogenic variation is not yet an established PALB2 disease mechanism. PM1 is not applicable to this truncating variant.	cspec
BP2	N/A	The PALB2 expert panel does not use BP2 in this framework. BP2 is not applicable.	cspec
PP2	N/A	The PALB2 expert panel does not use PP2 because missense variation is not an established disease mechanism. PP2 is not applicable.	cspec
PS3	N/A	The PALB2 expert panel does not apply PS3 for protein functional assays in this framework. PS3 is therefore not applicable.	cspec
BP3	N/A	This criterion is not used by the PALB2 expert panel for this variant type. BP3 is not applicable.	cspec
PS2	N/A	The PALB2 expert panel does not use PS2 for this disorder framework. PS2 is not applicable.	cspec
BP5	N/A	The PALB2 expert panel does not use BP5 in this framework. BP5 is not applicable.	cspec
BP6	N/A	This criterion is not used by the PALB2 expert panel. BP6 is not applicable.	cspec
PP5	N/A	This criterion is not used by the PALB2 expert panel. PP5 is not applicable.	cspec

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