Variant classification summary

NM_024675.4:c.2469C>G

PALB2 · NP_078951.2:p.(Leu823=) · NM_024675.4

GRCh37: chr16:23641006 G>C · GRCh38: chr16:23629685 G>C

Gene: PALB2 Transcript: NM_024675.4

Final call

Likely Benign

BP7 supporting BP4 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Leu823=)

gnomAD AF

3.716983890591818e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.2469C>G (p.Leu823=) variant has been reported in ClinVar predominantly as likely benign or benign, and no expert panel submission was identified.

2

In gnomAD v4.1, this variant is present at 6/1,614,212 alleles overall (0.00037%) with a highest observed population frequency of 5/62,506 alleles (0.00800%) in Remaining individuals; it is absent from gnomAD v2.1.

3

This synonymous variant is predicted to have no meaningful effect on splicing, with a SpliceAI maximum delta score of 0.00; under the PALB2 specification, this supports BP4 and is consistent with BP7.

Final determination: Rule19 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 Likely Benign.

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
BS4	Not assessed	No quantitative non-segregation data were identified. The PALB2 specification requires LOD or likelihood ratio evidence to apply BS4.	cspec
PM4	N/A	This is a synonymous substitution, and the PALB2 specification states that PM4 is not used for this variant type.	cspec
PM3	Not assessed	No Fanconi anemia proband data or confirmed in trans occurrences with a pathogenic PALB2 variant were identified, so PM3 cannot be scored.	cspec
BP6	N/A	BP6 is not used in this PALB2 expert specification.	cspec
BP5	N/A	BP5 is not applied for PALB2 in this expert specification.	cspec
BP1	N/A	This variant is synonymous, not missense. The PALB2 specification applies BP1 to missense variants only.	cspec
BS3	N/A	BS3 is not used in this PALB2 expert specification for this context.	cspec
BS2	Not assessed	No qualifying observations in unaffected adults with the required PALB2-specific point-based framework were identified, so BS2 cannot be applied.	cspec
BS1	Not met	Population frequency does not reach the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.00800% (5/62,506), which is below the >0.01% threshold.	gnomad_v4 cspec
PP4	N/A	PP4 is not applied for PALB2-related cancer predisposition in this expert specification.	cspec
PM6	N/A	PM6 is not applied for PALB2 in this expert specification.	cspec
PM2	Not met	This variant is not rare enough for PM2_Supporting under the PALB2 specification. In gnomAD v4.1, the overall frequency is 0.00037% (6/1,614,212), which is above the ≤0.000333% threshold, and the highest observed population frequency is 0.00800% (5/62,506).	gnomad_v4 cspec
PM1	N/A	PM1 is not used for PALB2 in this expert specification.	cspec
PS4	Not assessed	No qualifying PALB2 case-control study showing a significant enrichment of this variant in affected individuals was identified.	cspec clinvar
BA1	Not met	Population frequency is far below the PALB2 BA1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.00800% (5/62,506), which is below the >0.1% threshold.	gnomad_v4 cspec
PP1	Not assessed	No segregation data were identified, so PP1 cannot be applied.	cspec
PVS1	Not met	This synonymous variant does not fall into the PALB2 PVS1 loss-of-function categories, and available splicing evidence does not indicate an abnormal splice effect. SpliceAI shows a maximum delta score of 0.00.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
BP7	Met	This is a synonymous PALB2 variant, and available computational evidence does not suggest an RNA splice defect. SpliceAI predicts no significant splice impact, with a maximum delta score of 0.00.	cspec spliceai
BP4	Met	Computational splicing evidence supports no impact on splicing. SpliceAI predicts a maximum delta score of 0.00, which is below the PALB2 BP4 threshold of ≤0.1.	cspec spliceai
BP2	N/A	BP2 is not applied for PALB2 in this expert specification.	cspec
PP2	N/A	PP2 is not used for PALB2 in this expert specification.	cspec
PS3	N/A	PS3 is not used in this PALB2 expert specification for this context.	cspec
BP3	N/A	BP3 is not used for PALB2 in this expert specification.	cspec
PP5	N/A	PP5 is not used in this PALB2 expert specification.	cspec
PP3	Not met	Computational evidence does not support a splice-altering effect. SpliceAI predicts a maximum delta score of 0.00, which is below the PALB2 PP3 threshold of ≥0.2.	cspec spliceai
PM5	N/A	PM5 is not applicable here because the PALB2 specification uses a truncation-cutoff PM5 rule rather than classic same-residue missense logic, and this variant is synonymous.	cspec pm5_candidates
PS2	N/A	PS2 is not applied for PALB2 in this expert specification.	cspec
PS1	Not assessed	No PALB2 PS1 splicing comparator evidence was identified to show that this variant produces the same established pathogenic splice effect as a known pathogenic variant.	cspec spliceai

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.