Variant classification summary

NM_024675.4:c.968C>T

PALB2 · NP_078951.2:p.(Ala323Val) · NM_024675.4

GRCh37: chr16:23646899 G>A · GRCh38: chr16:23635578 G>A

Gene: PALB2 Transcript: NM_024675.4

Final call

PM2 supporting BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Ala323Val)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.968C>T (p.Ala323Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar as a variant of uncertain significance.

2

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

3

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.03, which is below the PALB2 PP3 splice threshold of 0.2.

4

As a missense variant in PALB2, this change meets BP1 because pathogenic missense variation is considered uncommon in this gene under the PALB2 specifications.

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
PVS1	Not met	This missense variant does not fall into the PALB2 loss-of-function PVS1 categories, and the generic PVS1 scaffold states that it is not a nonsense, frameshift, or canonical ±1,2 splice variant. SpliceAI also predicts no significant splice impact with a maximum delta score of 0.03, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	Available evidence does not support PS1. PALB2 PS1 is not used for missense changes, and no evidence was identified that this variant matches a qualifying PALB2 splicing-table entry.	cspec spliceai
PS2	N/A	PALB2 specifications state that PS2 should not be used for this gene-disease setting, and no informative confirmed de novo evidence was identified.	cspec
PS3	N/A	PALB2 specifications do not use PS3 for this setting. No well-established functional evidence was identified that would override the gene-specific rule.	cspec
PS4	Not assessed	This variant has been reported in ClinVar as uncertain significance, but no case-control study was identified showing a significant enrichment in affected individuals with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3 or lower 95% confidence interval ≥1.5. Therefore PS4 is not currently assessed.	cspec clinvar
PM1	N/A	PALB2 specifications state that PM1 should not be used because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed population frequency is therefore 0, which is below the PALB2 PM2_Supporting threshold of ≤1/300,000 (0.000333%), so PM2_Supporting is met.	cspec gnomad_v4 gnomad_v2
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic PALB2 variant in individuals with Fanconi anemia, so PM3 cannot be assessed.	cspec
PM4	N/A	This is a missense substitution, not a stop-loss variant, and PALB2 specifications state that PM4 is not applicable for in-frame changes less than a single exon.	cspec
PM5	Not met	Available evidence does not support PM5. PALB2 applies PM5 only to truncating variants with premature termination codons upstream of p.Tyr1183 or to qualifying splice variants with observed RNA evidence, and this variant is neither.	cspec spliceai
PM6	N/A	PALB2 specifications state that PM6 should not be used for this gene-disease setting, and no assumed de novo evidence was identified.	cspec
PP1	Not assessed	No quantitative segregation data were identified for this variant, so the PALB2 LOD-score or Bayes factor thresholds for PP1 cannot be evaluated.	cspec
PP2	N/A	PALB2 specifications state that PP2 should not be used because missense variation is not an established disease mechanism for PALB2.	cspec
PP3	Not met	Available evidence does not support PP3. For PALB2, PP3 is not used for missense prediction, and splice-based PP3 requires SpliceAI ≥0.2; this variant has a maximum SpliceAI delta score of 0.03, which is below that threshold.	cspec spliceai
PP4	N/A	PALB2 specifications state that PP4 should not be used for the autosomal dominant cancer predisposition setting because the phenotype is genetically heterogeneous and not sufficiently specific.	cspec
PP5	N/A	PALB2 specifications state that PP5 is not for use in this VCEP framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so the observed population frequency is 0, which is below the PALB2 BA1 threshold of >0.1%. BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1, so the observed population frequency is 0, which is below the PALB2 BS1 threshold of >0.01%. BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No data were identified showing this variant in healthy individuals meeting the PALB2 Fanconi anemia BS2 point-based framework, so BS2 cannot be assessed.	cspec
BS3	N/A	PALB2 specifications do not use BS3 for this setting. No well-established functional evidence was identified that would support a benign functional code under the PALB2 framework.	cspec
BS4	Not assessed	No quantitative non-segregation data were identified for this variant, so the PALB2 BS4 LOD-score or Bayes factor thresholds cannot be evaluated.	cspec
BP1	Met	This variant is a missense substitution, and PALB2 specifications apply BP1 to all missense variants because pathogenic missense variation is considered very uncommon in this gene. Therefore BP1 is met at Supporting strength.	cspec
BP2	N/A	PALB2 specifications mark BP2 as not applicable, and no qualifying cis/trans observation framework was identified for use here.	cspec
BP3	N/A	This is not an in-frame insertion or deletion, and PALB2 specifications state that BP3 is not applicable.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact with a maximum delta score of 0.03, which is at or below the PALB2 BP4 splice threshold of ≤0.1. However, PALB2 specifications state that BP4 should not be applied for missense variants, so BP4 is not met.	cspec spliceai
BP5	N/A	PALB2 specifications state that BP5 should not be used for this gene because co-occurrence with other pathogenic variants does not provide reliable benign evidence in this setting.	cspec
BP6	N/A	PALB2 specifications state that BP6 is not for use in this VCEP framework.	cspec
BP7	N/A	This is a missense variant rather than a synonymous or deep intronic change, and no RNA study showing lack of aberrant splicing was identified. BP7 is therefore not applicable.	cspec spliceai

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