Variant classification summary

NM_024675.3:c.2787_2788dup

PALB2 · NP_078951.2:p.(Asn930IlefsTer6) · NM_024675.3

GRCh37: chr16:23635375 T>TTA · GRCh38: chr16:23624054 T>TTA

Gene: PALB2 Transcript: NM_024675.3

Final call

Pathogenic

PVS1 very strong PM2 supporting PM5 supporting PP5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Asn930IlefsTer6)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.2787_2788dup (p.Asn930IlefsTer6; p.N930Ifs*6) variant has been reported in ClinVar as pathogenic, including an expert panel submission.

2

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

3

This frameshift duplication is predicted to create p.(Asn930IlefsTer6), introducing a premature termination codon consistent with loss of function in a gene where loss of function is an established disease mechanism, and it truncates the protein upstream of p.Tyr1183, supporting PVS1 and PM5_Supporting under the PALB2 specification.

4

SpliceAI shows a maximum delta score of 0.20, which suggests possible splice impact, but this was not applied as a separate PP3 or BP4 pathogenic criterion for this frameshift variant under the PALB2 rule set.

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 generate p.(Asn930IlefsTer6) [p.(N930Ifs*6)] with a premature termination codon well upstream of the last exon, which is consistent with nonsense-mediated decay. PALB2 loss of function is an established disease mechanism, and the PALB2 specification directs use of the PALB2 PVS1 decision tree, so PVS1 is met at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 is not applicable because this is a frameshift variant, and the PALB2 PS1 rule is reserved for specific splicing comparisons rather than truncating variants of this type.	cspec
PS2	N/A	PS2 is not applicable because the PALB2 specification does not use de novo evidence for this context, and no informative confirmed de novo occurrence was identified.	cspec
PS3	N/A	PS3 is not applicable under the PALB2 specification for this protein-truncating variant. No variant-specific functional assay evidence was needed beyond the PALB2 loss-of-function framework already captured by PVS1.	cspec oncokb
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study was identified showing a significant enrichment in affected individuals that meets 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 clinvar
PM1	N/A	PM1 is not applicable because the PALB2 specification does not use this criterion for PALB2 variants in this setting.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v4.1, which is below the PALB2 PM2_Supporting threshold of ≤0.000333% (1 in 300,000). It is also absent from gnomAD v2.1, supporting rarity in population databases.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No evidence was identified that this variant was observed in trans with another pathogenic PALB2 variant in a proband with the relevant recessive Fanconi anemia phenotype, so PM3 cannot be assessed from the available data.	cspec PMID:17200671
PM4	N/A	PM4 is not applicable because the PALB2 specification does not use PM4 for this type of variant and reserves PM4 for stop-loss variants only.	cspec
PM5	Met	The predicted truncating effect, p.(Asn930IlefsTer6), occurs upstream of p.Tyr1183. Under the PALB2 specification, truncating variants with premature termination codons upstream of p.Tyr1183 meet PM5 at supporting strength.	cspec pvs1_variant_assessment
PM6	N/A	PM6 is not applicable because the PALB2 specification does not use assumed de novo evidence in this setting, and no relevant de novo observation was identified.	cspec
PP1	Not assessed	No segregation data were identified for this variant. The PALB2 specification requires quantitative co-segregation evidence or defined affected-relative thresholds, so PP1 cannot be applied from the available information.	cspec
PP2	N/A	PP2 is not applicable because the PALB2 specification does not use PP2.	cspec
PP3	N/A	SpliceAI shows a maximum delta score of 0.20, which reaches the PALB2 splice-prediction threshold used for PP3. However, this rule is intended for silent, missense, in-frame, or eligible intronic variants, and this frameshift variant is already captured by PVS1, so PP3 is not applied separately.	cspec spliceai
PP4	N/A	PP4 is not applicable because PALB2-related cancer predisposition does not have a sufficiently specific phenotype for use of this criterion in the autosomal dominant setting.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
BA1	Not met	This variant is absent from gnomAD v4.1 (0%), which is below the PALB2 BA1 threshold of >0.1%, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1 (0%), which is below the PALB2 BS1 threshold of >0.01%, so BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing this variant in healthy adults or in the PALB2 recessive evidence framework at the point thresholds required for BS2, so this criterion cannot be assessed.	cspec
BS3	N/A	BS3 is not applicable under the PALB2 specification for this variant type. No well-established assay evidence showing no damaging effect was identified.	cspec oncokb
BS4	Not assessed	No non-segregation data were identified for this variant. The PALB2 specification requires quantitative evidence such as a negative LOD score or low Bayes factor, so BS4 cannot be applied from the available information.	cspec
BP1	N/A	BP1 is not applicable because this is not a missense variant.	cspec
BP2	N/A	BP2 is not applicable because the PALB2 specification does not use this criterion in this setting, and no qualifying cis/trans observation was identified.	cspec
BP3	N/A	BP3 is not applicable because this is not an in-frame change in a repetitive region without known function.	cspec
BP4	Not met	SpliceAI shows a maximum delta score of 0.20, which is above the PALB2 BP4 no-impact threshold of ≤0.1. This does not support benign computational evidence, so BP4 is not met.	cspec spliceai
BP5	N/A	BP5 is not applicable because the PALB2 specification does not use this criterion.	cspec
BP6	N/A	BP6 is not applicable because this criterion is not used by the PALB2 expert panel.	cspec
BP7	N/A	BP7 is not applicable because this is not a synonymous or deep intronic variant, and no RNA evidence showing lack of aberrant splicing was identified.	cspec

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