Variant classification summary

NM_024675.3:c.109C>A

PALB2 · NP_078951.2:p.(Arg37Ser) · NM_024675.3

GRCh37: chr16:23649273 G>T · GRCh38: chr16:23637952 G>T

Gene: PALB2 Transcript: NM_024675.3

Final call

Likely Benign

BS1 strong BP1 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Arg37Ser)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.109C>A (p.Arg37Ser; p.R37S) variant has been reported in ClinVar with an expert-panel classification of uncertain significance, alongside additional clinical laboratory submissions of uncertain significance and likely benign.

2

This variant is present in gnomAD v4.1 at 16/1,612,736 alleles (AF 0.00099%), with a highest observed African/African American subpopulation frequency of 0.01603%, which is above the PALB2 BS1 threshold of 0.01% and below the BA1 threshold of 0.1%.

3

SpliceAI predicts no meaningful splice effect for this variant (max delta score 0.00), which does not meet the PALB2 PP3 splicing threshold of 0.2 and does not support RNA-based PVS1 application.

4

REVEL (0.195) and BayesDel (0.120598) were noted, but the PALB2 VCEP does not use missense protein predictors for PP3 or BP4, while BP1 is applied to PALB2 missense variants under this framework.

Final determination: Rule18 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 missense variant does not fall into a PALB2 loss-of-function variant class for default PVS1 use, and no RNA evidence or splice prediction supports a loss-of-function transcript effect. SpliceAI showed a max delta score of 0.00, so available evidence does not support applying PVS1.	cspec pvs1_gene_context pvs1_variant_assessment spliceai
PS1	Not met	Available evidence does not show that this variant matches a PALB2 pathogenic splicing-equivalence entry, and the PALB2 VCEP does not use PS1 for missense changes. Therefore PS1 is not met.	cspec spliceai
PS2	N/A	The PALB2 VCEP does not use PS2 for this disease setting, and no informative confirmed de novo evidence is available for this variant.	cspec
PS3	N/A	The PALB2 VCEP does not use PS3 for this setting, and no reviewed variant-specific functional evidence was identified that would override that framework here.	cspec oncokb
PS4	Not assessed	This variant has been reported in ClinVar, but no case-control study was identified showing a significant increase in affected individuals that meets the PALB2 PS4 threshold of p≤0.05 with OR, HR, or RR ≥3 or lower 95% CI ≥1.5. Therefore PS4 remains unassessed.	cspec clinvar
PM1	N/A	PM1 is not used by the PALB2 VCEP because missense pathogenic variation is not yet confirmed as a disease mechanism for PALB2. Cancer Hotspots also did not identify a significant hotspot at this residue.	cspec hotspots
PM2	Not met	This variant is present in gnomAD v4.1 at 16/1,612,736 alleles (AF 0.00099%), which is above the PALB2 PM2_Supporting threshold of 0.000333%. Therefore PM2 is not met.	cspec gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in an individual with Fanconi anemia, so PM3 remains unassessed.	cspec clinvar
PM4	N/A	This variant is a missense substitution, not a stop-loss variant, and PM4 is not applicable under the PALB2 VCEP framework.	cspec
PM5	N/A	The PALB2 VCEP does not use PM5 for missense changes. This variant is a missense substitution without evidence for a truncating or qualifying splice-loss mechanism, so PM5 is not applicable.	cspec spliceai
PM6	N/A	The PALB2 VCEP does not use PM6 for this disease setting, and no assumed de novo evidence was identified for this variant.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so there is no basis to calculate the PALB2 PP1 LOD or Bayes factor thresholds. PP1 remains unassessed.	cspec clinvar
PP2	N/A	The PALB2 VCEP does not use PP2 because missense variation is not an established disease mechanism for PALB2.	cspec
PP3	Not met	SpliceAI predicts no significant splice impact for this variant, with a max delta score of 0.00, which is below the PALB2 PP3 splicing threshold of 0.2. REVEL was 0.195 and BayesDel was 0.120598, but the PALB2 VCEP does not use missense protein predictors for PP3. Therefore PP3 is not met.	cspec spliceai revel bayesdel
PP4	N/A	PP4 is not applicable under the PALB2 VCEP framework for the autosomal dominant cancer-predisposition setting because the phenotype is not sufficiently specific to PALB2 alone.	cspec
PP5	N/A	PP5 is not used by this VCEP, so external assertions alone are not applied as evidence here.	cspec clinvar
BA1	Not met	The highest observed gnomAD v4.1 subpopulation frequency is 0.01603% in the African/African American population, which is below the PALB2 BA1 threshold of 0.1%. Therefore BA1 is not met.	cspec gnomad_v4
BS1	Met	This variant is present in gnomAD v4.1 with a highest observed subpopulation frequency of 0.01603% in the African/African American population, which is above the PALB2 BS1 threshold of 0.01%. This supports BS1 at strong strength.	cspec gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adults under the PALB2 Fanconi anemia BS2 point-based framework. Therefore BS2 remains unassessed.	cspec
BS3	N/A	The PALB2 VCEP does not use BS3 for this setting. No reviewed RNA study supporting an alternative RNA-based benign code was identified for this exact variant.	cspec oncokb
BS4	Not assessed	No non-segregation data were identified for this variant, so the PALB2 BS4 LOD or Bayes factor thresholds cannot be evaluated. BS4 remains unassessed.	cspec clinvar
BP1	Met	This is a missense variant, and the PALB2 VCEP applies BP1 to all missense variants because pathogenic missense changes are thought to be exceedingly rare in PALB2 relative to truncating disease-causing variants. This supports BP1 at supporting strength.	cspec
BP2	N/A	BP2 is not applicable under the PALB2 VCEP framework for this setting.	cspec
BP3	N/A	This variant is not an in-frame insertion or deletion in a repetitive region, and BP3 is not applicable under the PALB2 VCEP framework.	cspec
BP4	N/A	Although SpliceAI predicts no splice effect with a max delta score of 0.00, the PALB2 VCEP does not apply BP4 to missense variants. Therefore BP4 is not applicable for this missense change.	cspec spliceai
BP5	N/A	BP5 is not applicable under the PALB2 VCEP framework.	cspec
BP6	N/A	BP6 is not used by this VCEP, so outside benign assertions are not applied as independent evidence here.	cspec clinvar
BP7	N/A	This variant is a missense substitution rather than a synonymous or deep intronic change, so BP7 is not applicable.	cspec

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