NM_024675.4:c.154G>A

PALB2 · NP_078951.2:p.(Val52Ile) · NM_024675.4

GRCh37: chr16:23649228 C>T · GRCh38: chr16:23637907 C>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.(Val52Ile)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.154G>A (p.Val52Ile) variant has been reported in ClinVar with conflicting single-submitter interpretations of uncertain significance and likely benign.

This variant is absent from gnomAD v2.1 and is present at very low overall frequency in gnomAD v4.1 (3/1,614,050 alleles; 0.00019%), but the highest observed subpopulation frequency is 0.00160% (1/62,510 alleles), which is above the PALB2 PM2 threshold exception and remains below the BS1 and BA1 population thresholds.

SpliceAI predicts no significant splice impact (max delta score 0.01), and REVEL (0.045) and BayesDel (-0.518425) are low; however, the PALB2 VCEP does not use PP3 or BP4 for missense variants, while BP1 is applicable to all PALB2 missense variants.

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 variant is a missense substitution, p.(Val52Ile), and does not fall into the PALB2 loss-of-function variant categories used for PVS1. Gene-level context supports loss of function as a disease mechanism in PALB2, but this specific change is not a nonsense, frameshift, or canonical splice-site variant, and SpliceAI predicts no significant splice effect (max delta score 0.01).	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	N/A	Available evidence does not support PS1. The PALB2 VCEP does not use PS1 for missense variants, and no evidence was identified that this nucleotide change causes the same pathogenic splicing effect as a previously established pathogenic variant.	cspec spliceai
PS2	N/A	This criterion is not used in the PALB2 VCEP framework for this disorder context.	cspec
PS3	N/A	This criterion is not used in the PALB2 VCEP framework for this variant type and disease context.	cspec
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study or other evidence showing significant enrichment in affected individuals was identified. Available evidence does not support the PALB2 PS4 threshold of p-value 0.05 or less with an odds ratio, hazard ratio, or relative risk of at least 3, or a lower 95% confidence interval of at least 1.5.	cspec clinvar
PM1	N/A	This criterion is not used for PALB2 because missense pathogenic variation is not an established mechanism of disease in this gene.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 and is very rare overall in gnomAD v4.1 (3/1,614,050 alleles; 0.00019%). However, the highest observed subpopulation frequency is 0.00160% (1/62,510 alleles) in Remaining individuals, which is above the PALB2 PM2 threshold of 0.000333% and falls under the VCEP exception for a singleton in an under-represented subpopulation, so PM2_Supporting is not applied.	cspec gnomad_v2 gnomad_v4
PM3	Not assessed	No evidence was identified that this variant has been observed in trans with a pathogenic PALB2 variant in a proband with Fanconi anemia or other qualifying recessive disease context. Available evidence does not support assigning PM3 points.	cspec
PM4	N/A	This criterion is not applicable because the PALB2 VCEP uses PM4 only for stop-loss variants, and this variant is a missense substitution.	cspec
PM5	N/A	This criterion is not applicable because the PALB2 VCEP does not use PM5 for missense variants. The PALB2-specific PM5 rule is limited to qualifying truncating or splice variants expected to create a premature termination codon upstream of p.Tyr1183.	cspec
PM6	N/A	This criterion is not used in the PALB2 VCEP framework for this disorder context.	cspec
PP1	Not assessed	No segregation data were identified for this variant. Available evidence does not support the PALB2 PP1 thresholds based on LOD score, Bayes factor, or affected-relative counts.	cspec
PP2	N/A	This criterion is not used for PALB2 because missense variation is not an established disease mechanism for this gene in the PALB2 VCEP framework.	cspec
PP3	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), below the PALB2 PP3 splicing threshold of 0.2. REVEL is 0.045 and BayesDel is -0.518425, but the PALB2 VCEP does not use PP3 for missense variants.	cspec spliceai revel bayesdel
PP4	N/A	This criterion is not used for PALB2-related cancer predisposition because the phenotype is not sufficiently specific for a single genetic etiology in the PALB2 VCEP framework.	cspec
PP5	N/A	This criterion is not for use in the PALB2 VCEP framework.	cspec
BA1	Not met	Population frequency is well below the PALB2 BA1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 2.8e-07 (0.000028%), which is below the BA1 threshold of 0.1%.	cspec gnomad_v4
BS1	Not met	Population frequency is below the PALB2 BS1 threshold. In gnomAD v4.1, the grpmax filtering allele frequency is 2.8e-07 (0.000028%), which is below the BS1 threshold of 0.01%.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified that this variant has been observed in the number of unaffected individuals required for PALB2 BS2 scoring. Population database observations are not sufficient for this criterion in the PALB2 framework.	cspec gnomad_v4
BS3	N/A	This criterion is not used in the PALB2 VCEP framework for this variant type and disease context.	cspec
BS4	Not assessed	No lack-of-segregation data were identified for this variant. Available evidence does not support the PALB2 BS4 thresholds based on LOD score or Bayes factor.	cspec
BP1	Met	This variant is a missense substitution, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense variation in PALB2 is considered exceedingly rare relative to truncating disease-causing variants.	cspec
BP2	N/A	This criterion is not used in the PALB2 VCEP framework.	cspec
BP3	N/A	This criterion is not used for PALB2 in the VCEP framework.	cspec
BP4	N/A	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), and REVEL and BayesDel scores are low at 0.045 and -0.518425, respectively. However, the PALB2 VCEP does not apply BP4 to missense variants, even when splice prediction is benign.	cspec spliceai revel bayesdel
BP5	N/A	This criterion is not used for PALB2 in the VCEP framework.	cspec
BP6	N/A	This criterion is not for use in the PALB2 VCEP framework.	cspec
BP7	N/A	This criterion is intended for synonymous or qualifying deep intronic variants, or for RNA evidence showing no splicing defect in those variant classes. This variant is a missense substitution.	cspec

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