Variant classification summary

NM_024675.3:c.2524_2535delinsTCAGA

PALB2 · NP_078951.2:p.(Ala842SerfsTer7) · NM_024675.3

GRCh37: chr16:23640576 AGGAAGCTCTGC>TCTGA · GRCh38: chr16:23629255 AGGAAGCTCTGC>TCTGA

Gene: PALB2 Transcript: NM_024675.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PP5 supporting PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Ala842SerfsTer7)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.2524_2535delinsTCAGA (p.(Ala842SerfsTer7)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as pathogenic, including an expert-panel pathogenic classification.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing it below the PALB2 PM2_Supporting population threshold of 0.000333%.

3

The predicted consequence is a frameshift with premature termination, p.(Ala842SerfsTer7), in a gene where loss of function is an established disease mechanism, supporting truncating-variant evidence under the PALB2 specification.

4

SpliceAI predicts no significant splice effect for this variant, with a maximum delta score of 0.10, supporting interpretation of the variant as a truncating allele rather than a splice-altering 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 frameshift variant is predicted to cause p.(Ala842SerfsTer7) / p.(A842Sfs*7), introducing a premature termination codon in exon 6 of 13 and well upstream of the last exon, which is consistent with nonsense-mediated decay of a PALB2 transcript in a gene where loss of function is an established disease mechanism. Available evidence supports applying PVS1 at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment
PS4	Not met	No case-control study was identified showing this exact variant is significantly enriched in affected individuals, so the PALB2 PS4 threshold is not met.	cspec clinvar
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed.	cspec
PM4	N/A	PM4 is not applicable in the PALB2 specification for this type of variant because this criterion is reserved for stop-loss variants and not for this frameshift delins.	cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another pathogenic PALB2 variant in a proband with Fanconi anemia, so PM3 cannot be assessed.	cspec
BP6	N/A	BP6 is not used in this VCEP framework.	cspec
BP5	N/A	BP5 is not applicable in the PALB2 specification.	cspec
BP1	N/A	BP1 applies to missense variants in PALB2, and this variant is a frameshift delins, so BP1 is not applicable.	cspec
BS3	N/A	BS3 is not applicable in the PALB2 VCEP framework for protein functional evidence, and no RNA rescue study relevant to a benign interpretation was identified.	cspec
BS2	Not assessed	No qualifying observations of this variant in healthy individuals under the PALB2 BS2 framework were identified, so BS2 cannot be assessed.	cspec
BS1	Not met	This variant is absent from gnomAD v4.1, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.	cspec gnomad_v4
PP4	N/A	PP4 is not applicable for autosomal dominant PALB2-related cancer predisposition in this framework.	cspec
PM6	N/A	PM6 is not applicable in the PALB2 specification.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its frequency is therefore below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%), so PM2_Supporting is met.	cspec gnomad_v4 gnomad_v2
PM1	N/A	PM1 is not applicable in the PALB2 specification.	cspec hotspots
BA1	Not met	This variant is absent from gnomAD v4.1, which is below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.	cspec gnomad_v4
BP7	N/A	BP7 applies to synonymous and deep intronic variants or RNA evidence showing lack of aberrant splicing for those classes, and this variant is a coding frameshift delins, so BP7 is not applicable.	cspec
BP4	Not assessed	SpliceAI predicts no significant splice impact with a maximum delta score of 0.10, which is at the PALB2 BP4 splice threshold. However, BP4 was not applied because this variant has an independent frameshift truncating effect and the lack of a splice effect does not support a benign overall interpretation.	cspec spliceai
BP2	N/A	BP2 is not applicable in the PALB2 specification.	cspec
PP2	N/A	PP2 is not applicable in the PALB2 specification.	cspec
PS3	N/A	PS3 is not applicable in the PALB2 VCEP framework for protein functional evidence, and no qualifying RNA assay was identified that would substitute for PVS1-based evidence.	cspec oncokb
BP3	N/A	BP3 is not applicable in the PALB2 specification.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
PP3	N/A	PALB2 PP3 for splicing applies to silent, missense, in-frame, or non-canonical intronic variants with predicted splice impact, and this variant is a frameshift delins. SpliceAI also does not show a qualifying splice signal, with a maximum delta score of 0.10 below the PP3 threshold of 0.20.	cspec spliceai
PM5	Met	This variant is a truncating frameshift predicted to introduce p.(Ala842SerfsTer7), which is upstream of the PALB2 VCEP truncation cutoff at p.Tyr1183*. This supports applying PM5_Supporting under the PALB2 specification.	cspec
PS2	N/A	PS2 is not applicable in the PALB2 specification.	cspec
PS1	Not assessed	No evidence was identified that this variant matches a PALB2 PS1 splicing-table entry, so PS1 was not assessed.	cspec

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