Variant classification summary

NM_024675.4:c.1042C>A

PALB2 · NP_078951.2:p.(Gln348Lys) · NM_024675.4

GRCh37: chr16:23646825 G>T · GRCh38: chr16:23635504 G>T

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Gln348Lys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.1042C>A (p.Gln348Lys; Q348K) variant has been reported in ClinVar with predominantly uncertain significance submissions, with additional likely benign and benign submissions.

2

This variant is present in gnomAD v4.1 at an overall allele frequency of 0.00304% (49/1,613,732 alleles) with a highest observed population frequency of 0.00415% in European non-Finnish individuals; this is below the PALB2 BS1 threshold of 0.01% and above the PM2 threshold of 0.000333%.

3

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, which is below the PALB2 PP3 splicing threshold of 0.2.

4

Because this is a PALB2 missense variant, BP1 is met at supporting strength under the PALB2 specification, while PVS1 is not met because the variant is not a truncating or canonical splice-site loss-of-function change.

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. The generic PVS1 scaffold states that c.1042C>A is not a nonsense, frameshift, or canonical ±1,2 splice variant, so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not met	No evidence was identified that this variant has the same established pathogenic protein or splicing consequence as a previously classified pathogenic PALB2 variant, so PS1 is not met.	cspec spliceai
PS2	N/A	This PALB2 specification does not use PS2 for this disease context, so PS2 is not applicable.	cspec
PS3	N/A	This PALB2 specification does not use PS3 for this variant assessment framework, so PS3 is not applicable.	cspec
PS4	Not met	This variant has been reported in ClinVar, but no qualifying case-control evidence was identified showing p-value ≤0.05 together with an odds ratio, hazard ratio, or relative risk ≥3, or a lower 95% confidence interval ≥1.5. PS4 is therefore not met.	cspec clinvar
PM1	N/A	The PALB2 specification does not use PM1, so PM1 is not applicable.	cspec
PM2	Not met	Population frequency does not meet the PALB2 PM2_Supporting threshold. In gnomAD v4.1, the variant has a grpmax filtering allele frequency of 0.003179%, which is above the PM2 threshold of 0.000333% (1/300,000), so PM2 is not met.	cspec gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in a proband informative for Fanconi anemia scoring, so PM3 could not be assessed.	cspec clinvar
PM4	N/A	This variant is a missense substitution, and the PALB2 specification does not apply PM4 to missense variants. PM4 is therefore not applicable.	cspec
PM5	N/A	The PALB2 PM5_Supporting rule is specified for truncating or qualifying splice variants upstream of p.Tyr1183, not for this missense variant, so PM5 is not applicable.	cspec
PM6	N/A	This PALB2 specification does not use PM6 in this disease context, so PM6 is not applicable.	cspec
PP1	Not assessed	No segregation data were identified to calculate a qualifying LOD score or Bayes factor for PALB2-related disease, so PP1 could not be assessed.	cspec
PP2	N/A	The PALB2 specification does not use PP2, so PP2 is not applicable.	cspec
PP3	Not met	SpliceAI predicts no splice effect for this variant, with a maximum delta score of 0.00. This is below the PALB2 PP3 splicing threshold of ≥0.2, so PP3 is not met.	cspec spliceai
PP4	N/A	The PALB2 specification does not use PP4 for the autosomal dominant cancer predisposition context, so PP4 is not applicable.	cspec
PP5	N/A	This PALB2 specification does not use PP5, so PP5 is not applicable.	cspec
BA1	Not met	Population frequency is far below the PALB2 BA1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 0.003179%, which is below the BA1 threshold of 0.1%, so BA1 is not met.	cspec gnomad_v4
BS1	Not met	Population frequency does not reach the PALB2 BS1 threshold. In gnomAD v4.1, the highest observed population frequency is 0.00415% in European non-Finnish individuals, which is below the BS1 threshold of 0.01%, so BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No qualifying observations were identified in unaffected individuals that would permit point-based BS2 scoring under the PALB2 Fanconi anemia framework. Population database observations alone are not sufficient for this criterion, so BS2 could not be assessed.	cspec
BS3	N/A	The PALB2 specification does not apply BS3 for protein functional evidence in this framework, so BS3 is not applicable.	cspec
BS4	Not assessed	No quantitative non-segregation data were identified to calculate a qualifying LOD score or Bayes factor, so BS4 could not be assessed.	cspec
BP1	Met	This variant is a missense substitution, and the PALB2 specification applies BP1 to all missense variants because pathogenic missense variants are thought to be exceedingly rare in this gene. BP1 is met at supporting strength.	cspec
BP2	N/A	The PALB2 specification does not use BP2, so BP2 is not applicable.	cspec
BP3	N/A	The PALB2 specification does not use BP3, so BP3 is not applicable.	cspec
BP4	N/A	Although SpliceAI predicts no splice impact for this variant with a maximum delta score of 0.00, the PALB2 specification states that BP4 should not be applied for missense variants. BP4 is therefore not applicable.	cspec spliceai
BP5	N/A	The PALB2 specification does not use BP5, so BP5 is not applicable.	cspec
BP6	N/A	The PALB2 specification does not use BP6, so BP6 is not applicable.	cspec
BP7	N/A	This variant is a missense substitution rather than a synonymous or deep intronic variant, so BP7 is not applicable.	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.