NM_024675.3:c.532del

PALB2 · NP_078951.2:p.(Glu178AsnfsTer15) · NM_024675.3

GRCh37: chr16:23647334 TC>T · GRCh38: chr16:23636013 TC>T

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.(Glu178AsnfsTer15)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.532del (p.(Glu178AsnfsTer15), p.(E178Nfs*15)) variant has not been observed in COSMIC and has been reported in ClinVar as Pathogenic, including expert panel review.

This variant is absent from gnomAD v4.1 and gnomAD v2.1, placing its observed population frequency at 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 and BA1 benign frequency thresholds.

This variant is a frameshift predicted to generate an early truncating protein product, and PALB2 loss of function is an established disease mechanism in the applicable VCEP framework, supporting a loss-of-function interpretation.

SpliceAI predicts no significant splice impact, with a maximum delta score of 0.05, which is below the PALB2 PP3 threshold of 0.2 and below the BP4 splice threshold of 0.1.

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, NM_024675.3:c.532del, predicted to cause p.(Glu178AsnfsTer15) / p.(E178Nfs*15). PALB2 loss of function is an established disease mechanism in the applicable PALB2 VCEP framework, and this early truncating change is consistent with a loss-of-function allele; therefore PVS1 is met at very strong strength.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	N/A	This is a frameshift variant, not a missense or splice-equivalent change eligible for the PALB2 PS1 splicing table, so PS1 is not applicable.	cspec
PS2	N/A	The PALB2 VCEP specification does not use PS2 for this disease setting, and no confirmed de novo evidence was identified.	cspec
PS3	N/A	The PALB2 VCEP specification does not apply PS3 for protein functional data in this setting, and no RNA assay evidence requiring a PVS1-strength RNA adjustment was identified here.	cspec spliceai
PS4	Not assessed	This variant has been reported in ClinVar, but no exact variant-specific case-control study or validated odds ratio meeting the PALB2 PS4 threshold was identified. Available evidence is insufficient to assess PS4.	clinvar cspec PMID:28779002
PM1	N/A	The PALB2 VCEP specification does not use PM1 because missense pathogenic variation in PALB2 is not an established disease mechanism, and this variant is a frameshift rather than a hotspot-based missense change.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. Its observed population frequency is therefore 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1 in 300,000), so PM2 is met at supporting strength.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No verified evidence was identified showing this variant in trans with another pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assessed from the available evidence.	cspec PMID:17200671
PM4	N/A	The PALB2 VCEP specification does not apply PM4 to frameshift variants; PM4 is reserved for stop-loss variants in this framework.	cspec
PM5	Met	The PALB2 VCEP specification allows PM5_Supporting for frameshifting or truncating variants with a premature termination codon upstream of p.Tyr1183. This variant is predicted to truncate the protein at p.(Glu178AsnfsTer15) / p.(E178Nfs*15), well upstream of p.Tyr1183, so PM5 is met at supporting strength.	cspec pvs1_variant_assessment
PM6	N/A	The PALB2 VCEP specification does not use PM6 in this disease setting, and no assumed de novo evidence was identified.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so the LOD or Bayes factor thresholds required for PALB2 PP1 could not be evaluated.	cspec
PP2	N/A	The PALB2 VCEP specification does not use PP2 because missense variation is not an established disease mechanism, and this variant is not missense.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.05. This is below the PALB2 PP3 threshold of 0.2, so available computational evidence does not support PP3.	cspec spliceai
PP4	N/A	The PALB2 VCEP specification does not use PP4 for the autosomal dominant hereditary cancer setting because the phenotype is not sufficiently specific.	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, so its observed population frequency is 0%. This is below the PALB2 BA1 threshold of greater than 0.1%, and BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1, so its observed population frequency is 0%. This is below the PALB2 BS1 threshold of greater than 0.01%, and BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in the number of unaffected or appropriately characterized individuals required for PALB2 BS2 scoring, so BS2 cannot be assessed.	cspec
BS3	N/A	The PALB2 VCEP specification does not apply BS3 for protein functional data in this setting, and no RNA study showing a lack of splicing impact was identified for use under the RNA-specific guidance.	cspec spliceai
BS4	Not assessed	No non-segregation data were identified for this variant, and the LOD or Bayes factor thresholds required for PALB2 BS4 were not available. BS4 cannot be assessed from the current evidence.	cspec
BP1	N/A	BP1 in the PALB2 specification applies to missense variants. This variant is a frameshift, so BP1 is not applicable.	cspec
BP2	N/A	The PALB2 VCEP specification does not use BP2 in this setting.	cspec
BP3	N/A	This is not an in-frame indel in a repetitive region, and BP3 is not applicable under the PALB2 specification.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.05, which is below the BP4 splice threshold of 0.1. However, this computational splice result does not override the damaging frameshift protein consequence, so BP4 is not applied.	cspec spliceai pvs1_variant_assessment
BP5	N/A	BP5 is not applicable under the PALB2 VCEP specification.	cspec
BP6	N/A	BP6 is not used by this VCEP framework.	cspec
BP7	N/A	BP7 is intended for synonymous or qualifying deep intronic variants. This variant is a frameshift coding deletion, so BP7 is not applicable.	cspec

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.