NM_024675.3:c.3249G>C

PALB2 · NP_078951.2:p.(Glu1083Asp) · NM_024675.3

GRCh37: chr16:23619286 C>G · GRCh38: chr16:23607965 C>G

Gene: PALB2 Transcript: NM_024675.3

Final call

Likely Benign

BS1 strong BP1 supporting BP6 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Glu1083Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.3249G>C (p.Glu1083Asp, p.E1083D) variant has been reported in ClinVar and is classified there as benign by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.

In gnomAD v4, the variant has a total allele frequency of 0.00533% and a grpmax filtering allele frequency of 0.088684%, which is above the PALB2 BS1 threshold of 0.01% but below the BA1 threshold of 0.1%.

Computational data predict no significant splice effect, with a SpliceAI max delta score of 0.00; REVEL is 0.081 and BayesDel is -0.49371, although PALB2 VCEP guidance does not apply missense PP3 or BP4 for this gene.

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
BA1	Not met	Population frequency does not meet the PALB2 BA1 threshold. In gnomAD v4, the grpmax filtering allele frequency is 0.088684%, which is below the BA1 threshold of >0.1%.	gnomad_v4 cspec
BS1	Met	Population frequency supports a benign interpretation. In gnomAD v4, the grpmax filtering allele frequency is 0.088684%, which is above the PALB2 BS1 threshold of >0.01%.	gnomad_v4 cspec
BS2	Not assessed	No data were identified showing this variant in informative unaffected individuals under the PALB2 BS2 point-based framework, so BS2 was not assessed.	cspec
BS3	N/A	BS3 is not applicable under the PALB2 VCEP framework for this variant. The PALB2 specification directs RNA evidence into BP7-variable or PVS1-related assessment rather than BS3.	cspec
BS4	Not assessed	No family study showing lack of segregation was identified, and no LOD score or Bayes factor was available for this variant, so BS4 was not assessed.	cspec
BP1	Met	This is a missense variant, NM_024675.3:c.3249G>C (p.Glu1083Asp, p.E1083D). Under the PALB2 VCEP specification, BP1 applies to all missense variants because pathogenic missense variation is thought to be exceedingly rare in PALB2.	cspec
BP2	N/A	BP2 is not applicable under the PALB2 VCEP framework.	cspec
BP3	N/A	BP3 is not applicable under the PALB2 VCEP framework because PALB2 is not considered to have a relevant repetitive region for this criterion.	cspec
BP4	N/A	Although SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the BP4 splice threshold of ≤0.1), the PALB2 VCEP does not apply BP4 to missense variants. REVEL (0.081) and BayesDel (-0.49371) were reviewed but are not used for PALB2 missense BP4 adjudication.	spliceai revel bayesdel cspec
BP5	N/A	BP5 is not applicable under the PALB2 VCEP framework.	cspec
BP6	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.	cspec clinvar
BP7	N/A	BP7 is intended for synonymous or qualifying deep intronic variants. This variant is a missense substitution, so BP7 is not applicable.	cspec
PM1	N/A	PM1 is not applicable under the PALB2 VCEP framework because missense pathogenic variation in PALB2 is not yet confirmed as a mechanism of disease.	cspec
PM2	Not met	Population frequency does not meet the PALB2 PM2_Supporting threshold. In gnomAD v4, the total allele frequency is 0.00533%, which is above the PM2_Supporting threshold of ≤0.000333%.	gnomad_v4 cspec
PM3	Not assessed	No evidence was identified that this variant was observed in trans with a pathogenic PALB2 variant in Fanconi anemia, so PM3 was not assessed.	cspec
PM4	N/A	PM4 is not applicable because this variant is not a stop-loss variant.	cspec
PM5	N/A	PM5 is not applicable because the PALB2 VCEP does not use PM5 for missense changes. This criterion is reserved for qualifying truncating or splice variants under the PALB2 specification.	cspec
PM6	N/A	PM6 is not applicable under the PALB2 VCEP framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, and no LOD score or Bayes factor was available, so PP1 was not assessed.	cspec
PP2	N/A	PP2 is not applicable under the PALB2 VCEP framework.	cspec
PP3	N/A	Although SpliceAI predicts no significant splice impact for this variant (max delta score 0.00, below the PP3 splice threshold of ≥0.2), the PALB2 VCEP does not apply PP3 to missense variants. REVEL (0.081) and BayesDel (-0.49371) were reviewed but are not used for PALB2 missense PP3 adjudication.	spliceai revel bayesdel cspec
PP4	N/A	PP4 is not applicable under the PALB2 VCEP framework for autosomal dominant PALB2-related cancer predisposition.	cspec
PP5	N/A	PP5 is not for use under the PALB2 VCEP framework.	cspec
PS1	N/A	PS1 is not applicable here because the PALB2 VCEP does not use PS1 for missense changes, and no evidence was identified that this variant causes the same splice effect as an established pathogenic variant.	cspec spliceai
PS2	N/A	PS2 is not applicable under the PALB2 VCEP framework.	cspec
PS3	N/A	PS3 is not applicable under the PALB2 VCEP framework for this variant. The PALB2 specification directs relevant RNA evidence into PVS1-related or BP7-related assessment rather than PS3.	cspec
PS4	Not assessed	No qualifying case-control evidence was identified for this variant. No odds ratio, relative risk, hazard ratio, or lower 95% confidence interval meeting the PALB2 PS4 threshold was available, so PS4 was not assessed.	clinvar cspec
PVS1	Not met	PVS1 was not applied. This variant is a missense substitution rather than a canonical null variant, it is not at a canonical ±1/2 splice site, and SpliceAI predicts no significant splice impact (max delta score 0.00). No RNA evidence showing an observed splice defect was identified.	cspec pvs1_gene_context pvs1_variant_assessment spliceai

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