Variant classification summary

NM_024675.4:c.1578T>C

PALB2 · NP_078951.2:p.(His526=) · NM_024675.4

GRCh37: chr16:23646289 A>G · GRCh38: chr16:23634968 A>G

Gene: PALB2 Transcript: NM_024675.4

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(His526=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.1578T>C (p.His526=) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar with benign or likely benign single-submitter classifications.

2

This variant is absent from gnomAD v2.1 and gnomAD v4.1, placing its observed population frequency at 0%, below the PALB2 PM2_Supporting threshold of 0.000333%.

3

In silico splice prediction shows no evidence of splice disruption, with a SpliceAI maximum delta score of 0.00; this is below the PALB2 BP4 threshold of 0.1 and well below the PP3 threshold of 0.2, supporting BP4 and BP7 rather than PP3.

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 into the PALB2 loss-of-function or canonical splice categories used for PVS1, and SpliceAI predicts no splice disruption (max delta score 0.00).	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not assessed	No evidence was identified that this variant matches a PALB2 PS1 splicing-table comparator with the same predicted or observed splice effect as an established pathogenic variant.	cspec spliceai
PS2	N/A	This criterion is not used for PALB2 in this framework.	cspec
PS3	N/A	This criterion is not used for PALB2 in this framework.	cspec
PS4	Not assessed	No case-control study or other quantitative enrichment data were identified showing that this variant is significantly more common in affected individuals than in controls. ClinVar contains benign or likely benign single-submitter assertions, but these do not satisfy the PALB2 PS4 requirement.	clinvar cspec
PM1	N/A	This criterion is not used for PALB2 because missense pathogenic variation is not established as a disease mechanism in this framework.	cspec
PM2	Met	This variant is absent from gnomAD v4.1 and gnomAD v2.1. The observed population frequency is therefore 0%, which is below the PALB2 PM2_Supporting threshold of 0.000333% (1 in 300,000).	gnomad_v4 gnomad_v2 cspec
PM3	Not assessed	No observations were identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 cannot be assessed from the available evidence.	cspec
PM4	N/A	This criterion is not used for this PALB2 variant type in this framework.	cspec
PM5	N/A	For PALB2, PM5 is a truncation-cutoff rule rather than a classic same-residue missense rule. This synonymous variant does not meet that framework-specific PM5 logic.	cspec pm5_candidates
PM6	N/A	This criterion is not used for PALB2 in this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so PALB2 PP1 cannot be assessed.	cspec
PP2	N/A	This criterion is not used for PALB2 because missense variation is not an established mechanism in this framework.	cspec
PP3	Not met	SpliceAI predicts no splice impact for this variant, with a maximum delta score of 0.00. This is below the PALB2 PP3 threshold of 0.2, so computational evidence does not support a damaging splicing effect.	spliceai cspec
PP4	N/A	This criterion is not used for PALB2-related cancer predisposition in this framework.	cspec
PP5	N/A	This criterion is not used in this framework.	cspec
BA1	Not met	This variant is absent from gnomAD v4.1, so its observed population frequency is 0%. This is below the PALB2 BA1 threshold of more than 0.1%, so BA1 is not met.	gnomad_v4 cspec
BS1	Not met	This variant is absent from gnomAD v4.1, so its observed population frequency is 0%. This is below the PALB2 BS1 threshold of more than 0.01%, so BS1 is not met.	gnomad_v4 cspec
BS2	Not assessed	No qualifying observations were identified in unaffected individuals that would allow BS2 scoring under the PALB2 Fanconi anemia framework.	cspec
BS3	N/A	This criterion is not used for PALB2 in this framework.	cspec
BS4	Not assessed	No quantitative non-segregation data were identified for this variant, so BS4 cannot be assessed.	cspec
BP1	N/A	This criterion applies to missense variants in PALB2. This variant is synonymous, not missense.	cspec
BP2	N/A	This criterion is not used for PALB2 in this framework.	cspec
BP3	N/A	This criterion is not used for PALB2 in this framework.	cspec
BP4	Met	SpliceAI predicts no splice impact for this variant, with a maximum delta score of 0.00. This is below the PALB2 BP4 threshold of 0.1, supporting no computational evidence for abnormal splicing.	spliceai cspec
BP5	N/A	This criterion is not used for PALB2 in this framework.	cspec
BP6	N/A	This criterion is not used in this framework.	cspec
BP7	Met	This variant is a synonymous change, p.(His526=), and SpliceAI predicts no splice impact with a maximum delta score of 0.00. Under the PALB2 specification, this supports BP7 at Supporting strength.	cspec spliceai clinvar

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.