Variant classification summary

NM_024675.3:c.3362del

PALB2 · NP_078951.2:p.(Gly1121ValfsTer3) · NM_024675.3

GRCh37: chr16:23614978 AC>A · GRCh38: chr16:23603657 AC>A

Gene: PALB2 Transcript: NM_024675.3

Final call

Likely Pathogenic

PVS1 strong PP5 supporting PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Gly1121ValfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 NM_024675.3:c.3362del (NP_078951.2:p.(Gly1121ValfsTer3), p.(G1121Vfs*3)) variant has been reported in ClinVar, including an expert panel likely pathogenic classification and multiple pathogenic or likely pathogenic clinical laboratory submissions.

2

In gnomAD v4.1, this variant is present at 13/1,613,660 alleles (AF 0.00081%) with highest observed frequency 0.00134% in African/African American individuals; this is below the PALB2 BS1 and BA1 thresholds but above the PALB2 PM2_Supporting threshold.

3

Published evidence supports PALB2 as a tumor suppressor gene in which truncating variants are disease-relevant, and this frameshift is predicted to truncate the protein upstream of the PALB2 p.Tyr1183 truncation boundary used for PM5_Supporting.

4

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00.

Final determination: Rule12 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
BS4	Not assessed	No quantitative non-segregation data were identified for this variant. The PALB2 specification requires a Bayes factor or LOD-based segregation assessment, and no family data meeting those thresholds were available.	cspec
PM4	N/A	This variant is a frameshift deletion, and the PALB2 specification states that PM4 is not used for this variant type.	cspec
PM3	Not assessed	No evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia or another recessive PALB2-related presentation, so PM3 could not be applied.	cspec PMID:17200671
BP6	N/A	BP6 is not used by this PALB2 expert specification.	cspec
BP5	N/A	BP5 is not used by the PALB2 specification because co-occurrence with other pathogenic variants is not considered informative enough for this gene.	cspec
BP1	N/A	BP1 is intended for missense variants, whereas this variant is a frameshift deletion.	cspec
BS3	N/A	BS3 is not used by this PALB2 expert specification for this type of evidence assessment.	cspec
BS2	Not assessed	No evidence was identified showing this variant in the healthy adult context or recessive point-based framework required for BS2, so the criterion could not be assessed.	cspec
BS1	Not met	The highest observed population frequency in gnomAD v4.1 was 0.00134% (1/74,796 alleles in African/African American individuals), which is below the PALB2 BS1 threshold of >0.01%, so BS1 is not met.	cspec gnomad_v4
PP4	N/A	PP4 is not used for autosomal dominant PALB2-related cancer predisposition in this specification.	cspec
PM6	N/A	PM6 is not used by this PALB2 expert specification.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at 13/1,613,660 alleles (AF 0.00081%), with highest observed frequency 0.00134% in African/African American individuals. These values are above the PALB2 PM2_Supporting threshold of ≤0.000333%, so PM2 is not met.	cspec gnomad_v4
PM1	N/A	PM1 is not used for PALB2 because pathogenic missense variation has not been established as a disease mechanism for this gene.	cspec hotspots
PS4	Not assessed	This variant has been reported in ClinVar, but no exact-variant case-control study, odds ratio, relative risk, or p-value meeting the PALB2 PS4 threshold was identified. Published data support increased breast cancer risk for truncating PALB2 variants as a group, but that does not establish PS4 for this specific variant.	cspec clinvar PMID:28779002
BA1	Not met	The highest observed population frequency in gnomAD v4.1 was 0.00134%, which is well below the PALB2 BA1 threshold of >0.1%, so BA1 is not met.	cspec gnomad_v4
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be applied.	cspec
PVS1	Met	This variant is a frameshift predicted to truncate PALB2 as p.(Gly1121ValfsTer3) / p.(G1121Vfs*3). Germline loss of function is an established disease mechanism for PALB2, and the PALB2 specification directs use of a gene-specific PVS1 decision tree. Because this is a distal truncating event and the PALB2 specification separately treats truncating variants upstream of p.Tyr1183 as clinically relevant, PVS1 is applied with downgrade from Very Strong to Strong pending exact confirmation of the PALB2 decision-tree node for this late truncation.	cspec pvs1_gene_context pvs1_variant_assessment PMID:17200671 PMID:21365267 PMID:28858227
BP7	N/A	BP7 is intended for synonymous or deep intronic variants, whereas this variant is an exonic frameshift deletion.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.00, below the PALB2 BP4 splicing threshold of ≤0.1. However, BP4 is not appropriate here because the variant itself causes a frameshift and predicted truncation, so the available computational evidence does not support no impact on the gene product.	cspec spliceai
BP2	N/A	BP2 is not used by this PALB2 expert specification.	cspec
PP2	N/A	PP2 is not used for PALB2 because missense variation is not an established disease mechanism for this gene, and this variant is not missense.	cspec
PS3	N/A	PS3 is not used by this PALB2 expert specification for this evidence type.	cspec
BP3	N/A	BP3 is not used for PALB2 under this specification.	cspec
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely pathogenic.	cspec clinvar
PP3	N/A	PP3 in the PALB2 specification is used for predicted splice impact in selected silent, missense, in-frame, or noncanonical intronic variants. This frameshift variant has a SpliceAI maximum delta score of 0.00 and does not fit the PP3 use case.	cspec spliceai
PM5	Met	The PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This frameshift is predicted as p.(Gly1121ValfsTer3), which truncates the protein upstream of p.Tyr1183, so PM5_Supporting is met.	cspec pvs1_variant_assessment
PS2	N/A	PS2 is not used by this PALB2 expert specification.	cspec
PS1	N/A	PS1 in PALB2 is restricted to the splicing table context and is not applicable to this frameshift deletion.	cspec

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