Variant classification summary

NM_024675.3:c.3054G>C

PALB2 · NP_078951.2:p.(Glu1018Asp) · NM_024675.3

GRCh37: chr16:23632742 C>G · GRCh38: chr16:23621421 C>G

Gene: PALB2 Transcript: NM_024675.3

Final call

Benign

BA1 stand-alone benign BP1 supporting BP6 supporting benign

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Glu1018Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.3054G>C (p.Glu1018Asp; E1018D) variant has been reported in ClinVar, where the aggregate classification is Benign with expert panel review.

2

This variant is present in gnomAD v4.1 at 214/1,614,106 alleles (AF 0.01326%), with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%), which is above the PALB2 BA1 threshold of 0.1%.

3

SpliceAI predicts no significant splice effect (max delta score 0.01), below the PALB2 PP3 splice threshold of 0.2; REVEL is 0.118 and BayesDel is -0.42024, and the PALB2 specification does not support missense PP3/BP4 use beyond its stated splice rules.

Final determination: Rule17 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 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 variant is a missense substitution, not a nonsense, frameshift, or canonical ±1,2 splice variant, and no RNA evidence was identified to show a loss-of-function splicing effect. Available evidence therefore does not support PVS1 for this PALB2 variant.	cspec pvs1_gene_context pvs1_variant_assessment
PS1	Not assessed	No evidence was identified showing that this nucleotide change has the same established pathogenic amino acid or splicing consequence as a previously classified pathogenic PALB2 variant under the PALB2 PS1 splicing framework.	cspec
PS2	N/A	The PALB2 specification does not use PS2 for this framework.	cspec
PS3	N/A	The PALB2 specification does not use PS3 in this framework, and no variant-specific validated functional assay evidence was identified for separate application.	cspec oncokb
PS4	Not met	No case-control study or exact-variant enrichment data were identified to show this variant is significantly more common in affected individuals than in controls. The observed population frequency is also well above the PALB2 PM2 threshold, so available evidence does not support PS4.	cspec gnomad_v4 clinvar
PM1	N/A	PM1 is not applicable in the PALB2 specification, and no hotspot evidence supports use of a mutational hotspot rule for this variant.	cspec hotspots
PM2	Not met	This variant is present in gnomAD v4.1 at 214/1,614,106 alleles (AF 0.01326%), which is above the PALB2 PM2_Supporting threshold of ≤0.000333%. Available population data therefore do not support PM2.	cspec gnomad_v4
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic PALB2 variant in Fanconi anemia cases, so PM3 could not be applied.	cspec
PM4	N/A	PM4 is not applicable because this variant is not a PALB2 stop-loss variant and the PALB2 specification does not use PM4 for this type of change.	cspec
PM5	N/A	The PALB2 specification restricts PM5 to frameshifting, truncating, or qualifying splice loss-of-function variants upstream of p.Tyr1183. This missense variant does not meet that rule.	cspec
PM6	N/A	The PALB2 specification does not use PM6 for this framework.	cspec
PP1	Not assessed	No segregation data were identified for this variant, so the available evidence does not support PP1 at any strength.	cspec
PP2	N/A	PP2 is not applicable in the PALB2 specification.	cspec
PP3	Not met	SpliceAI predicts no significant splice effect for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of ≥0.2. REVEL is 0.118 and BayesDel is -0.42024, but the PALB2 specification does not support missense PP3 use outside its stated splice rule, so available computational evidence does not support PP3.	cspec spliceai revel bayesdel
PP4	N/A	PP4 is not applicable in the PALB2 specification.	cspec
PP5	N/A	PP5 is not applicable in the PALB2 specification.	cspec
BA1	Met	This variant is present in gnomAD v4.1 with highest observed East Asian frequency 187/44,876 alleles (AF 0.41670%) and grpmax FAF 0.36785%, both above the PALB2 BA1 threshold of >0.1%. This population frequency supports BA1.	cspec gnomad_v4
BS1	Not assessed	The observed gnomAD v4.1 population frequency exceeds the stricter BA1 threshold, so BS1 was not separately counted.	cspec gnomad_v4
BS2	Not assessed	No point-based evidence from unaffected individuals or qualifying Fanconi anemia context was identified, so BS2 could not be applied.	cspec
BS3	N/A	BS3 is not applicable in the PALB2 specification, and no qualifying benign functional assay evidence was identified for separate use.	cspec oncokb
BS4	Not assessed	No non-segregation data or quantitative evidence showing lack of segregation in affected relatives were identified, so BS4 could not be applied.	cspec
BP1	Met	This variant is a missense substitution, and the PALB2 specification states that BP1 applies to all missense variants. This supports BP1.	cspec
BP2	N/A	BP2 is not applicable in the PALB2 specification.	cspec
BP3	N/A	BP3 is not applicable in the PALB2 specification.	cspec
BP4	N/A	Although SpliceAI predicts no significant splice effect (max delta score 0.01), the PALB2 specification does not apply BP4 to missense variants in this context. BP4 was therefore not applied.	cspec spliceai
BP5	N/A	BP5 is not applicable in the PALB2 specification.	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 used for synonymous or qualifying deep intronic variants, and this variant is a missense substitution. BP7 is therefore not applicable.	cspec

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