NM_024675.3:c.104T>C

PALB2 · NP_078951.2:p.(Leu35Pro) · NM_024675.3

GRCh37: chr16:23649395 A>G · GRCh38: chr16:23638074 A>G

Gene: PALB2 Transcript: NM_024675.3

Final call

PM2 supporting BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Leu35Pro)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.104T>C (p.Leu35Pro) variant has not been observed in COSMIC and has been reported in ClinVar with an overall expert-panel classification of uncertain significance, alongside individual clinical laboratory submissions of likely pathogenic and uncertain significance.

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.0000619617% (1/1613900 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.

In published functional studies, p.(Leu35Pro) disrupted the BRCA1-PALB2 interaction, impaired homologous recombination and homology-directed repair, reduced RAD51 foci formation, and increased sensitivity to cisplatin and PARP inhibition, findings consistent with a damaging effect on PALB2 function.

In silico splice prediction does not support an RNA effect, with SpliceAI showing a maximum delta score of 0.01; REVEL (0.35) and BayesDel (0.236696) scores are available, but the PALB2 specification does not use missense predictor data for PP3 or BP4.

Final determination: Rule31 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 Uncertain Significance - Conflicting Evidence.

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.(Leu35Pro), and does not fall into the PALB2 or generic PVS1 null-variant categories. SpliceAI predicts no significant splice effect with a maximum delta score of 0.01, so available evidence does not support a predicted or observed loss-of-function mechanism for this variant.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	This variant is a missense change, and the PALB2 specification states PS1 should not be used for missense variants. No splice-table evidence was identified showing that this nucleotide change has the same established splice effect as a previously classified pathogenic variant.	cspec spliceai
PS2	N/A	This criterion is not applicable in the PALB2 specification because informative de novo observations are not used for PALB2-related disease assessment.	cspec
PS3	N/A	Published functional studies report damaging effects for p.(Leu35Pro), including loss of BRCA1-PALB2 interaction, homologous recombination defects, reduced RAD51 foci, and increased sensitivity to cisplatin and PARP inhibition. However, the PALB2 specification marks PS3 as not applicable, so these data are not coded as PS3 in this framework.	cspec PMID:28319063 PMID:31636395
PS4	Not assessed	This variant has been reported in ClinVar and one publication described segregation in a family with breast cancer, but no case-control study with p-value less than or equal to 0.05 and odds ratio, hazard ratio, or relative risk greater than or equal to 3 was identified. Available evidence is insufficient to determine whether affected-case prevalence is significantly increased over controls.	cspec clinvar PMID:28319063
PM1	N/A	This criterion is not applicable for PALB2 because missense pathogenic variation in PALB2 is not treated as an established mechanism for PM1-based hotspot or domain interpretation in this specification.	cspec
PM2	Met	This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 6.196170766466323e-07 (0.0000619617%; 1/1613900 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333% (1/300000). This supports PM2 at supporting strength.	cspec gnomad_v2 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 cannot be evaluated from the available data.	cspec
PM4	N/A	This criterion is not applicable because the variant is not a stop-loss change, and the PALB2 specification does not use PM4 for in-frame changes less than a single exon.	cspec
PM5	Not met	This variant is a missense change, and the PALB2 specification states PM5 should not be used for missense variants. No qualifying truncating or splice-related scenario for PALB2 PM5_Supporting was identified.	cspec
PM6	N/A	This criterion is not applicable in the PALB2 specification because de novo observations are not used for PALB2-related disease assessment.	cspec
PP1	Not assessed	One publication states that this variant segregated in a family with a strong history of breast cancer, but no quantitative segregation data such as LOD score or Bayes factor were identified. This is not enough to assign PP1 under the PALB2 specification.	cspec PMID:28319063
PP2	N/A	This criterion is not applicable because the PALB2 specification does not use PP2 for missense variants.	cspec
PP3	Not met	REVEL (0.35) and BayesDel (0.236696) scores are available, but the PALB2 specification states PP3 should not be used for missense predictor data. For splicing, SpliceAI shows a maximum delta score of 0.01, which is below the PALB2 PP3 threshold of 0.2, so computational evidence does not support PP3.	cspec spliceai revel bayesdel
PP4	N/A	This criterion is not applicable because PALB2-related cancer predisposition does not have a sufficiently specific phenotype for PP4 in the autosomal dominant setting under this specification.	cspec
PP5	N/A	This criterion is not used by the PALB2 specification.	cspec
BA1	Not met	The highest observed population frequency for this variant in gnomAD v4.1 is 0.000084763% (1/1179760 alleles in the non-Finnish European population), which is far below the PALB2 BA1 threshold of greater than 0.1%. This does not support BA1.	cspec gnomad_v4
BS1	Not met	The highest observed population frequency for this variant in gnomAD v4.1 is 0.000084763% (1/1179760 alleles), which is below the PALB2 BS1 threshold of greater than 0.01%. This does not support BS1.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy individuals meeting the PALB2 BS2 point-based framework, so BS2 cannot be assessed from the available data.	cspec
BS3	N/A	Although published studies report abnormal rather than normal function for p.(Leu35Pro), the PALB2 specification marks BS3 as not applicable. Functional evidence is therefore not coded as BS3 in this framework.	cspec PMID:28319063 PMID:31636395
BS4	Not assessed	No quantitative evidence of lack of segregation such as a negative LOD score or Bayes factor was identified for this variant, so BS4 cannot be assessed from the available data.	cspec
BP1	Met	This variant is a missense substitution, p.(Leu35Pro), and the PALB2 specification applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism in PALB2.	cspec clinvar
BP2	N/A	This criterion is not applicable in the PALB2 specification.	cspec
BP3	N/A	This criterion is not applicable because the variant is not an in-frame insertion or deletion in a repetitive region, and the PALB2 specification does not use BP3 for PALB2.	cspec
BP4	Not met	SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below the BP4 splice threshold of 0.1. However, the PALB2 specification states BP4 should not be applied for missense variants, so this does not support BP4 for p.(Leu35Pro).	cspec spliceai
BP5	N/A	This criterion is not applicable in the PALB2 specification.	cspec
BP6	N/A	This criterion is not used by the PALB2 specification.	cspec
BP7	N/A	This variant is a missense substitution rather than a synonymous or deep intronic change, so the PALB2 BP7 framework 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.