NM_024675.4:c.3132A>T

PALB2 · NP_078951.2:p.(Gln1044His) · NM_024675.4

GRCh37: chr16:23625394 T>A · GRCh38: chr16:23614073 T>A

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Gln1044His)

gnomAD AF

1.3647185516117947e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.3132A>T (p.Gln1044His) variant has not been identified as a statistically significant cancer hotspot and has been reported in ClinVar as a variant of uncertain significance with 5 clinical laboratory submissions.

This variant is present in population databases, including gnomAD v4.1 at 0.00136% overall (22/1612054 alleles) with a highest observed population frequency of 0.00989% in South Asian individuals, which is above the PALB2 PM2_Supporting threshold of 0.000333% but below the BS1 threshold of 0.01% and the BA1 threshold of 0.1%.

Computational evidence does not suggest a splice-disrupting effect, with a SpliceAI maximum delta score of 0.02, and this value is below the PALB2 PP3 splicing threshold of 0.2; additional missense predictor scores were REVEL 0.227 and BayesDel -0.259388.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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	Not met	This missense variant does not fall into the PALB2 loss-of-function variant categories used for PVS1, and the available splicing data do not show a splice-disrupting effect that would support a PVS1-based loss-of-function interpretation.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No evidence was identified that this variant produces the same established pathogenic protein or splice consequence as a previously classified PALB2 variant, and the specific PALB2 PS1 splicing-table comparison was not available in the retrieved materials.	cspec clinvar spliceai
PS2	N/A	The PALB2 specification does not use PS2 for this gene-disease context.	cspec
PS3	N/A	The PALB2 specification does not use PS3 for this gene, so no pathogenic functional criterion was applied in this review.	cspec
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study or exact affected-versus-control enrichment statistic meeting the PALB2 PS4 threshold was identified.	cspec clinvar
PM1	N/A	The PALB2 specification does not use PM1 because missense pathogenic variation has not been established as a mechanism suitable for this rule in PALB2.	cspec hotspots
PM2	Not met	This variant is present in gnomAD v4.1 at 0.00136% (22/1612054 alleles), which is above the PALB2 PM2_Supporting threshold of 0.000333%, so PM2 is not met.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an informative Fanconi anemia context, so PM3 could not be assessed.	cspec clinvar
PM4	N/A	This is a missense substitution, and the PALB2 specification limits PM4 to stop-loss variants rather than missense changes.	cspec
PM5	N/A	The PALB2 PM5 rule is a truncation-cutoff framework and does not apply to this missense variant.	cspec pm5_candidates
PM6	N/A	The PALB2 specification does not use PM6 for this gene-disease context.	cspec
PP1	Not assessed	No segregation data, LOD score, or Bayes factor was identified for this variant, so PP1 could not be applied.	cspec clinvar
PP2	N/A	The PALB2 specification does not use PP2 because missense variation has not been established as a suitable mechanism for this criterion in PALB2.	cspec
PP3	Not met	SpliceAI predicts no meaningful splice effect for this variant, with a maximum delta score of 0.02, which is below the PALB2 PP3 splicing threshold of 0.2, so PP3 is not met.	cspec spliceai revel bayesdel
PP4	N/A	The PALB2 specification does not use PP4 for autosomal dominant PALB2-related cancer predisposition because the phenotype is not sufficiently specific for this criterion.	cspec
PP5	N/A	The PALB2 specification does not use PP5.	cspec
BA1	Not met	The highest observed gnomAD v4.1 population frequency is 0.00989% in South Asian individuals, which is well below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	The highest observed gnomAD v4.1 population frequency is 0.00989% in South Asian individuals, which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No qualifying observations in unaffected individuals meeting the PALB2 BS2 point-based framework were identified.	cspec gnomad_v4 gnomad_v2
BS3	N/A	The PALB2 specification does not use BS3 for this gene.	cspec
BS4	Not assessed	No quantitative non-segregation evidence, negative LOD score, or Bayes factor meeting the PALB2 BS4 framework was identified.	cspec clinvar
BP1	Met	This variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic PALB2 variants are predominantly truncating and true pathogenic missense variants are thought to be very uncommon.	cspec
BP2	N/A	The PALB2 specification does not use BP2 for this gene-disease context.	cspec
BP3	N/A	The PALB2 specification does not use BP3 for this gene.	cspec
BP4	N/A	Although SpliceAI predicts no significant splice impact with a maximum delta score of 0.02, the PALB2 specification does not apply BP4 to missense variants, so BP4 is not applied here.	cspec spliceai
BP5	N/A	The PALB2 specification does not use BP5 for this gene-disease context.	cspec
BP6	N/A	The PALB2 specification does not use BP6.	cspec
BP7	N/A	This criterion is intended for synonymous or deep intronic variants, whereas this variant is a missense substitution.	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.