NM_024675.3:c.2831T>A

PALB2 · NP_078951.2:p.(Ile944Asn) · NM_024675.3

GRCh37: chr16:23635333 A>T · GRCh38: chr16:23624012 A>T

Gene: PALB2 Transcript: NM_024675.3

Final call

BP1 supporting PM2 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Ile944Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.2831T>A (p.Ile944Asn) variant has been reported in ClinVar and is currently classified there as uncertain significance, including an expert-panel ClinGen submission.

This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), which is below the PALB2 PM2_Supporting threshold of 0.000333%.

No variant-specific reviewed functional evidence was identified in the retrieved materials, and the PALB2 expert specification does not apply PS3 or BS3 in this framework.

SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01; REVEL was 0.449 and BayesDel was -0.120213, but the PALB2 expert specification does not apply PP3 or BP4 to missense variants.

Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.

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
BA1	Not met	This variant is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), with a highest observed population frequency of 0.00111% in South Asian individuals, which is below the PALB2 BA1 threshold of >0.1%.	gnomad_v4 cspec
BS1	Not met	This variant is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), with a highest observed population frequency of 0.00111% in South Asian individuals, which is below the PALB2 BS1 threshold of >0.01%.	gnomad_v4 cspec
BS2	Not assessed	No data were identified showing the number of unaffected individuals or point-based evidence required to apply BS2 for PALB2-related Fanconi anemia.	cspec
BS3	N/A	The PALB2 expert specification does not use BS3 for this gene, so benign functional evidence was not applied in this framework.	cspec
BS4	Not assessed	No non-segregation data, LOD score, or Bayes factor were identified for this variant, so BS4 could not be assessed.	cspec
BP1	Met	This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants.	cspec
BP2	N/A	The PALB2 expert specification does not use BP2 for this gene.	cspec
BP3	N/A	The PALB2 expert specification does not use BP3 for this gene.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, which is below the BP4 splicing threshold of <=0.1. However, the PALB2 expert specification states that BP4 should not be applied to missense variants. REVEL was 0.449 and BayesDel was -0.120213, but these scores do not override the PALB2 missense rule.	cspec spliceai revel bayesdel
BP5	N/A	The PALB2 expert specification does not use BP5 for this gene.	cspec
BP6	N/A	The PALB2 expert specification does not use BP6 for this gene.	cspec
BP7	N/A	This variant is a missense substitution rather than a synonymous or qualifying deep intronic variant, so BP7 is not applicable.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 could not be assessed.	cspec
PP2	N/A	The PALB2 expert specification does not use PP2 for this gene.	cspec
PP3	N/A	SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, which is below the PALB2 PP3 splicing threshold of >=0.2. REVEL was 0.449 and BayesDel was -0.120213, but the PALB2 expert specification states that PP3 should not be applied to missense variants.	cspec spliceai revel bayesdel
PP4	N/A	The PALB2 expert specification does not use PP4 for this gene.	cspec
PP5	N/A	The PALB2 expert specification does not use PP5 for this gene.	cspec
PM1	N/A	The PALB2 expert specification does not use PM1 for this gene.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 3/1,577,962 alleles (0.00019%), which is below the PALB2 PM2 threshold of <=0.000333%. This supports rarity in the general population.	gnomad_v2 gnomad_v4 cspec
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 could not be assessed.	cspec
PM4	N/A	This variant is a missense substitution, and the PALB2 expert specification does not apply PM4 to this variant type.	cspec
PM5	N/A	This variant is a missense substitution. The PALB2 expert specification limits PM5 to qualifying truncating or splice variants expected to create a premature termination codon upstream of p.Tyr1183, so PM5 is not applicable.	cspec
PM6	N/A	The PALB2 expert specification does not use PM6 for this gene.	cspec
PS1	N/A	The PALB2 expert specification applies PS1 using a PALB2 splicing table. SpliceAI predicts no significant splice impact for this variant with a maximum delta score of 0.01, and no evidence was identified showing the same pathogenic splicing consequence as a known pathogenic variant.	cspec spliceai
PS2	N/A	The PALB2 expert specification does not use PS2 for this gene.	cspec
PS3	N/A	The PALB2 expert specification does not use PS3 for this gene, so pathogenic functional evidence was not applied in this framework.	cspec
PS4	Not assessed	This variant has been reported in ClinVar, including an expert-panel submission, but no case-control study, odds ratio, or other quantified enrichment data specific to this variant were identified to support PS4.	clinvar cspec
PVS1	Not met	Loss of function is an established PALB2 disease mechanism, but this variant is a missense substitution rather than a nonsense, frameshift, or canonical +/-1,2 splice variant. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, so available evidence does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
BS1_supporting_placeholder	N/A	No PALB2-specific supporting-level BS1 rule was provided beyond the defined BS1 threshold, so no separate supporting assessment was made.	cspec

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