Variant classification summary

NM_024675.3:c.1794G>A

PALB2 · NP_078951.2:p.(Leu598=) · NM_024675.3

GRCh37: chr16:23641681 C>T · GRCh38: chr16:23630360 C>T

Gene: PALB2 Transcript: NM_024675.3

Final call

Likely Benign

BS1 strong BP4 supporting BP6 supporting benign BP7 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Leu598=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.1794G>A (p.Leu598=) variant has been reported in ClinVar with an expert panel Likely Benign classification and additional benign or likely benign clinical laboratory submissions.

2

In gnomAD v4.1, this variant is present at 47/1614132 alleles (0.00291%) with a grpmax filtering allele frequency of 0.04713%, which is above the PALB2 BS1 threshold of 0.01%; gnomAD v2.1 also shows the variant in population databases, including African/African American individuals.

3

SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1 and below the PP3 threshold of 0.2.

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
PVS1	Not met	This synonymous PALB2 variant does not fall into the default loss-of-function variant classes for PVS1, and available splicing evidence does not support a loss-of-function transcript. SpliceAI predicts no significant splice impact with a maximum delta score of 0.06, so PVS1 is not supported.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	Available evidence does not identify that this variant produces the same established pathogenic splicing effect as another PALB2 variant. SpliceAI predicts no significant splice impact, so PS1 is not supported on the current evidence.	cspec spliceai
PS2	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PS3	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PS4	Not assessed	No case-control study, odds ratio, or quantified enrichment data were identified for this variant, so PS4 cannot be assessed from the available evidence.	clinvar cspec
PM1	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PM2	Not met	This variant is present in gnomAD v4.1 at 47/1614132 alleles (0.00291%), which is above the PALB2 PM2_Supporting threshold of 1/300000 (0.000333%). PM2 is therefore not met.	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic PALB2 variant in a proband meeting the Fanconi anemia scoring framework, so PM3 cannot be assessed.	cspec
PM4	N/A	This criterion is not applicable in the PALB2 VCEP specification for this variant type.	cspec
PM5	N/A	This synonymous variant does not meet the PALB2 PM5 framework, which is reserved for qualifying truncating or splice variants expected to create a premature termination codon upstream of p.Tyr1183.	cspec
PM6	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 cannot be assessed.	cspec clinvar
PP2	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PP3	Not met	Computational splicing evidence does not support a damaging effect. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 PP3 threshold of 0.2, so PP3 is not met.	spliceai cspec
PP4	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
PP5	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BA1	Not met	The gnomAD v4.1 grpmax filtering allele frequency is 0.04713%, which is below the PALB2 BA1 threshold of 0.1%, so BA1 is not met.	gnomad_v4 cspec
BS1	Met	This variant exceeds the PALB2 BS1 threshold in gnomAD v4.1. The grpmax filtering allele frequency is 0.04713%, which is above the BS1 threshold of 0.01%, supporting BS1 at strong strength.	gnomad_v4 gnomad_v2 cspec
BS2	Not assessed	No scored observations in unaffected individuals or other BS2 point-based evidence were identified, so BS2 cannot be assessed.	cspec
BS3	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 cannot be assessed.	cspec clinvar
BP1	N/A	This PALB2 rule applies only to missense variants. This variant is synonymous, so BP1 is not applicable.	cspec
BP2	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BP3	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BP4	Met	Computational splicing evidence supports no effect on splicing. SpliceAI predicts a maximum delta score of 0.06, which is below the PALB2 BP4 threshold of 0.1, so BP4 is met at supporting strength.	spliceai cspec
BP5	N/A	This criterion is not applicable in the PALB2 VCEP specification.	cspec
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Likely benign.	cspec clinvar
BP7	Met	This is a synonymous PALB2 variant, and available computational evidence predicts no meaningful splice effect. SpliceAI shows a maximum delta score of 0.06, which is consistent with no significant splice impact, so BP7 is met at supporting strength.	cspec spliceai

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