Variant classification summary

NM_024675.3:c.135G>A

PALB2 · NP_078951.2:p.(Lys45=) · NM_024675.3

GRCh37: chr16:23649247 C>T · GRCh38: chr16:23637926 C>T

Gene: PALB2 Transcript: NM_024675.3

Final call

Likely Benign

PM2 supporting BP4 supporting BP6 supporting benign BP7 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Lys45=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.135G>A (p.Lys45=) variant has been reported in ClinVar with an expert panel classification of likely benign.

2

This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%) with a highest observed population frequency of 0.00017% and grpmax FAF 2.8e-07, which is below the PALB2 PM2_Supporting threshold of 0.000333% and below the BS1 and BA1 benign frequency thresholds.

3

SpliceAI predicts no significant splice impact for this synonymous variant, with a maximum delta score of 0.00, which supports BP4 and argues against PP3 or a splice-based loss-of-function interpretation.

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 variant does not fall within the PALB2 loss-of-function variant categories used for PVS1, and available splicing evidence does not support a loss-of-function effect. SpliceAI predicts no significant splice impact (max delta score 0.00), so PVS1 is not met.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No evidence was identified showing that this variant has the same established pathogenic splicing effect as a previously classified pathogenic PALB2 variant, so PS1 was not assessed.	cspec spliceai
PS2	N/A	De novo evidence is not used for PALB2 under this specification, so PS2 is not applicable.	cspec
PS3	N/A	Functional-study evidence is not used for PALB2 under this specification, so PS3 is not applicable.	cspec
PS4	Not met	This variant has been reported in ClinVar, but no case-control study or statistically significant enrichment in affected individuals was identified. The available evidence does not support PS4.	cspec clinvar
PM1	N/A	PM1 is not applicable for PALB2 under this specification.	cspec
PM2	Met	This variant is present in gnomAD v4.1 at 2/1,614,022 alleles (AF 0.00012%), which is below the PALB2 PM2_Supporting threshold of 0.000333%. This supports PM2 at supporting strength.	cspec gnomad_v4
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable because this variant is not a stop-loss variant, and the PALB2 specification does not use PM4 for small in-frame changes.	cspec
PM5	N/A	This synonymous variant is not a truncating variant upstream of p.Tyr1183 and no RNA data were identified showing a qualifying loss-of-function splice effect, so PM5 is not applicable.	cspec spliceai
PM6	N/A	PM6 is not applicable for PALB2 under this specification.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PP1 was not assessed.	cspec clinvar
PP2	N/A	PP2 is not applicable for PALB2 under this specification.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this synonymous variant (max delta score 0.00), which is below the PALB2 PP3 threshold of 0.2. Therefore, PP3 is not met.	cspec spliceai
PP4	N/A	PP4 is not applicable for PALB2 under this specification.	cspec
PP5	N/A	PP5 is not applicable for PALB2 under this specification.	cspec
BA1	Not met	The gnomAD v4.1 filtering allele frequency is far below the PALB2 BA1 threshold of greater than 0.1%. Therefore, BA1 is not met.	cspec gnomad_v4
BS1	Not met	The gnomAD v4.1 frequency is below the PALB2 BS1 threshold of greater than 0.01%. Therefore, BS1 is not met.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in the number of unaffected individuals required by the PALB2 Fanconi anemia BS2 framework, so BS2 was not assessed.	cspec
BS3	N/A	BS3 is not applicable for PALB2 under this specification.	cspec
BS4	Not assessed	No non-segregation data were identified for this variant, so BS4 was not assessed.	cspec clinvar
BP1	N/A	BP1 applies to missense variants under this specification, and this variant is synonymous, so BP1 is not applicable.	cspec
BP2	N/A	BP2 is not applicable for PALB2 under this specification.	cspec
BP3	N/A	BP3 is not applicable for PALB2 under this specification.	cspec
BP4	Met	SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 BP4 threshold of 0.1. This supports BP4 at supporting strength.	cspec spliceai
BP5	N/A	BP5 is not applicable for PALB2 under this 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 synonymous PALB2 variant has no predicted splice effect, with SpliceAI max delta score 0.00. Under the PALB2 specification, this supports BP7 at supporting strength.	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.