Variant classification summary

NM_024675.3:c.3512del

PALB2 · NP_078951.2:p.(Leu1171CysfsTer20) · NM_024675.3

GRCh37: chr16:23614828 CA>C · GRCh38: chr16:23603507 CA>C

Gene: PALB2 Transcript: NM_024675.3

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Leu1171CysfsTer20)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.3512del (p.(Leu1171CysfsTer20), p.(L1171Cfs*20)) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as uncertain significance by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of 0.000333% and does not meet the BA1 (>0.1%) or BS1 (>0.01%) population thresholds.

3

PALB2 loss of function is an established disease mechanism, and the PALB2 specification states that variants predicted to escape nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still receive full PVS1; this terminal frameshift alters that WD40 tail.

4

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 and within the BP4 splice threshold of 0.1, although that splice prediction does not remove concern for the protein-disrupting frameshift effect.

Final determination: Rule19 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 Likely 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 in PALB2, a gene in which loss of function is an established disease mechanism. Although the altered transcript is expected to escape nonsense-mediated decay because the change is in the terminal coding exon, the PALB2 specification states that variants escaping nonsense-mediated decay but disrupting the indispensable C-terminal WD40 domain can still be granted full PVS1; this frameshift alters the WD40 tail and replaces the clinically relevant terminal residues.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This criterion is specified for PALB2 splice variants using the PALB2 PS1 splicing table. This variant is a terminal frameshift rather than a same-effect splice substitution.	cspec
PS2	N/A	The PALB2 specification does not use PS2 for autosomal dominant or autosomal recessive PALB2-related disease because informative de novo occurrences have not been established for this framework.	cspec
PS3	N/A	The PALB2 specification does not apply PS3 for protein functional assays in this framework, and no RNA study for this specific variant was identified that would support a PVS1_RNA-style application.	cspec
PS4	Not met	Published data support PALB2 truncating variants as a risk class, but no case-control study or exact-variant enrichment data were identified for c.3512del that meet the PALB2 PS4 threshold of p-value ≤0.05 with odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5.	cspec PMID:28779002 clinvar
PM1	N/A	The PALB2 specification states that PM1 should not be used because missense pathogenic variation is not yet confirmed as a disease mechanism, and this variant is not being interpreted under a PALB2 hotspot/domain PM1 framework.	cspec
PM2	Met	This variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333%. It is also absent from gnomAD v2.1, supporting rarity in population databases.	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	No evidence was identified that this variant has been observed in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 could not be evaluated.	cspec
PM4	N/A	The PALB2 specification restricts PM4 to stop-loss variants and does not use PM4 for this frameshift variant.	cspec
PM5	Not met	The PALB2 specification applies PM5_Supporting to frameshifting or truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift changes the terminal coding sequence and extends beyond the normal stop rather than creating a premature stop upstream of p.Tyr1183, so the PM5 rule is not met.	cspec pvs1_variant_assessment
PM6	N/A	The PALB2 specification does not use PM6 for PALB2-related disease.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so the quantitative PALB2 PP1 thresholds could not be evaluated.	cspec clinvar
PP2	N/A	The PALB2 specification states that PP2 should not be used.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.01. This is below the PALB2 PP3 splice threshold of ≥0.2, so PP3 is not met.	spliceai cspec
PP4	N/A	The PALB2 specification does not use PP4 for autosomal dominant PALB2-related cancer predisposition because the phenotype is not sufficiently specific.	cspec
PP5	N/A	This criterion is not used by the ClinGen PALB2 specification.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1 and therefore does not meet the PALB2 BA1 threshold of group maximum filtering allele frequency >0.1%.	gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v4.1 and therefore does not meet the PALB2 BS1 threshold of group maximum filtering allele frequency >0.01%.	gnomad_v4 cspec
BS2	Not assessed	No evidence was identified that this variant has been observed in the healthy-state configurations required for the PALB2 BS2 point-based framework, so BS2 could not be evaluated.	cspec
BS3	N/A	The PALB2 specification does not apply BS3 for protein functional assays in this framework.	cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant, so the PALB2 BS4 quantitative thresholds could not be evaluated.	cspec clinvar
BP1	N/A	The PALB2 BP1 rule applies to missense variants. This variant is a frameshift.	cspec
BP2	N/A	The PALB2 specification does not use BP2.	cspec
BP3	N/A	The PALB2 specification does not use BP3 for this type of variant.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact, with a maximum delta score of 0.01, which is within the PALB2 BP4 splice threshold of ≤0.1. However, this prediction addresses splicing only and does not indicate no impact on the gene product because the variant remains a protein-altering frameshift, so BP4 was not applied.	spliceai cspec
BP5	N/A	The PALB2 specification states that BP5 should not be used.	cspec
BP6	N/A	This criterion is not used by the ClinGen PALB2 specification.	cspec
BP7	N/A	The PALB2 BP7 rule applies to synonymous and deep intronic variants, or to RNA studies showing no splice defect for those variant classes. This variant is a coding frameshift.	cspec

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