NM_024675.3:c.338C>T

PALB2 · NP_078951.2:p.(Pro113Leu) · NM_024675.3

GRCh37: chr16:23647529 G>A · GRCh38: chr16:23636208 G>A

Gene: PALB2 Transcript: NM_024675.3

Final call

PM2 supporting BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Pro113Leu)

gnomAD AF

ClinVar

Uncertain Significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.338C>T (p.Pro113Leu) variant has been reported in ClinVar, where the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer expert panel classified it as uncertain significance, with additional submissions of uncertain significance and likely benign.

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed frequency below the PALB2 PM2_Supporting threshold of 1/300,000 (0.000333%).

SpliceAI predicts no splice impact with a max delta score of 0.00, and missense predictors are low (REVEL 0.012; BayesDel -0.722131); however, the PALB2 expert specification does not use PP3 or BP4 for missense prediction and applies BP1_Supporting to all 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
PVS1	Not met	This missense variant does not meet PALB2 PVS1 criteria. PALB2 loss of function is an established disease mechanism, but c.338C>T (p.Pro113Leu) is not a nonsense, frameshift, or canonical ±1,2 splice variant, and SpliceAI predicts no splice effect (max delta score 0.00), so the available evidence does not support a PVS1-based loss-of-function classification.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	This criterion is not applied for this missense variant because the PALB2 expert specification states that PS1 should not be used for missense changes and instead reserves PS1 for qualifying splice comparisons.	cspec
PS2	N/A	This criterion is not applicable because the PALB2 expert specification does not use de novo evidence for PALB2 autosomal dominant or autosomal recessive disease assessment.	cspec
PS3	N/A	This criterion is not applicable in the PALB2 expert framework. No variant-specific functional study was identified that would override this specification for protein-level PS3 use.	cspec oncokb
PS4	Not assessed	This variant has been reported in ClinVar, including an expert panel uncertain significance classification, but no case-control study or exact-variant enrichment data were identified to show a statistically significant increase in affected individuals. Therefore PS4 cannot be applied from the available evidence.	cspec clinvar
PM1	N/A	This criterion is not applicable because the PALB2 expert specification does not use PM1; missense pathogenic variation in PALB2 is not yet established as a disease mechanism, and no hotspot evidence supports this residue.	cspec hotspots
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed frequency is therefore 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 evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in a Fanconi anemia context, and no PM3 point-based proband data were available. PM3 is not applied.	cspec
PM4	N/A	This criterion is not applicable because c.338C>T is a missense substitution, not a stop-loss variant, and the PALB2 expert specification limits PM4 use to stop-loss variants.	cspec
PM5	N/A	This criterion is not applied for this variant. In PALB2, PM5 is repurposed for qualifying truncating or splice variants upstream of p.Tyr1183 and is specifically not used for missense changes such as p.Pro113Leu.	cspec pm5_candidates
PM6	N/A	This criterion is not applicable because the PALB2 expert specification does not use assumed de novo evidence for PALB2 disease assessment.	cspec
PP1	Not assessed	No segregation data were identified for this variant, and no LOD score, Bayes factor, or affected-relative count was available to meet PALB2 PP1 thresholds. PP1 is not applied.	cspec clinvar
PP2	N/A	This criterion is not applicable because the PALB2 expert specification does not use PP2; missense variation is not an established PALB2 disease mechanism for this purpose.	cspec
PP3	N/A	This criterion is not applied for this missense variant. SpliceAI predicts no splice impact (max delta score 0.00, below the PALB2 PP3 splice threshold of 0.2), and the PALB2 expert specification states that PP3 should not be used for missense prediction. REVEL is 0.012 and BayesDel is -0.722131, but these missense predictor results do not support PP3 use in this framework.	cspec spliceai revel bayesdel
PP4	N/A	This criterion is not applicable because the PALB2 expert specification does not use PP4 for autosomal dominant PALB2-related cancer predisposition, as the phenotype is not sufficiently specific to PALB2 alone.	cspec
PP5	N/A	This criterion is not applicable because PP5 is not used by the PALB2 expert specification.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so its observed population frequency is below the PALB2 BA1 threshold of greater than 0.1%. BA1 is not met.	cspec gnomad_v4
BS1	Not met	This variant is absent from gnomAD v4.1, so its observed population frequency is below the PALB2 BS1 threshold of greater than 0.01%. BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified that this variant was observed in healthy individuals under the PALB2 BS2 point-based framework, and population database absence cannot be used for BS2. BS2 is not applied.	cspec gnomad_v4
BS3	N/A	This criterion is not applicable in the PALB2 expert framework for this variant, and no variant-specific benign functional study was identified for an alternate approved route to use.	cspec oncokb
BS4	Not assessed	No non-segregation data, negative LOD score, or Bayes factor was identified for this variant. Therefore BS4 cannot be applied from the available evidence.	cspec clinvar
BP1	Met	This variant is a missense substitution, and the PALB2 expert specification applies BP1 to all missense variants because pathogenic missense variants in PALB2 are thought to be exceedingly rare. BP1_Supporting is met.	cspec
BP2	N/A	This criterion is not applicable because the PALB2 expert specification does not use BP2 in this framework.	cspec
BP3	N/A	This criterion is not applicable because c.338C>T is not an in-frame insertion or deletion, and the PALB2 expert specification does not use BP3 for PALB2.	cspec
BP4	N/A	This criterion is not applied for this missense variant. SpliceAI predicts no splice impact (max delta score 0.00, below the PALB2 BP4 splice threshold of 0.1), and REVEL (0.012) and BayesDel (-0.722131) are low, but the PALB2 expert specification states that BP4 should not be used for missense variants.	cspec spliceai revel bayesdel
BP5	N/A	This criterion is not applicable because the PALB2 expert specification does not use BP5.	cspec
BP6	N/A	This criterion is not applicable because BP6 is not used by the PALB2 expert specification.	cspec
BP7	N/A	This criterion is not applicable because c.338C>T is a missense variant rather than a synonymous or deep intronic variant, which are the variant types addressed by PALB2 BP7.	cspec

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