Variant classification summary

NM_024675.3:c.682C>T

PALB2 · NP_078951.2:p.(Gln228Ter) · NM_024675.3

GRCh37: chr16:23647185 G>A · GRCh38: chr16:23635864 G>A

Gene: PALB2 Transcript: NM_024675.3

Final call

Pathogenic

PM2 supporting PVS1 very strong PP5 supporting PM5 supporting

Variant details

Gene

PALB2

Transcript

NM_024675.3

Protein

NP_078951.2:p.(Gln228Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The PALB2 c.682C>T (p.Gln228Ter; p.Q228*) variant has been reported in ClinVar as pathogenic, including review by the ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel.

2

This variant is absent from gnomAD v2.1 and is present only once in gnomAD v4.1 at an overall allele frequency of 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%.

3

This variant introduces a premature stop codon early in PALB2, and published PALB2 studies together with the PALB2 specification support loss of function as an established disease mechanism for hereditary cancer predisposition.

4

SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which does not support PP3 and is consistent with the primary consequence being protein truncation rather than altered splicing.

Final determination: Rule4 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 Pathogenic.

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
BS4	Not assessed	No family-based nonsegregation data, LOD score, or likelihood ratio were identified for this variant, so the PALB2 BS4 thresholds cannot be evaluated.	cspec
PM4	N/A	This variant is a nonsense substitution, not a stop-loss variant, and PALB2 does not use PM4 for this variant type.	cspec pvs1_variant_assessment
PM3	Not assessed	No biallelic Fanconi anemia case data or confirmed in trans observations with another pathogenic PALB2 variant were identified for this variant, so PM3 cannot be scored.	cspec PMID:17200671
BP6	N/A	BP6 is not used by this PALB2 specification.	cspec
BP5	N/A	BP5 is not used for PALB2 because co-occurring pathogenic variants do not reliably exclude a contribution from PALB2-related cancer predisposition.	cspec
BP1	N/A	BP1 applies to missense variants. This variant is a nonsense change and does not meet the PALB2 BP1 use case.	cspec pvs1_variant_assessment
BS3	N/A	BS3 is not used for PALB2 in this specification for the present variant context.	cspec
BS2	Not assessed	No qualifying observations were identified in healthy adults that would allow point-based BS2 assessment for this variant. The single gnomAD observation does not satisfy PALB2 BS2 because population cohorts are not used for this rule.	cspec gnomad_v4
BS1	Not met	The highest observed gnomAD v4.1 population frequency is 0.00008% (1/1,180,014 alleles in European non-Finnish), which is below the PALB2 BS1 threshold of greater than 0.01%, so BS1 is not met.	gnomad_v4 cspec
PP4	N/A	PP4 is not used for PALB2-related autosomal dominant cancer predisposition because the phenotype is not sufficiently specific for a single genetic cause.	cspec
PM6	N/A	PM6 is not used for PALB2 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 0.00006% (1/1,614,016 alleles), which is below the PALB2 PM2_Supporting threshold of 0.000333%, so PM2_Supporting is met.	gnomad_v2 gnomad_v4 cspec
PM1	N/A	PM1 is not used for PALB2 because missense pathogenic variation in defined hotspot domains is not an established disease mechanism for this specification.	cspec hotspots
PS4	Not assessed	Published studies support increased cancer risk for truncating PALB2 variants as a class, but no exact variant-specific case-control dataset with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥3 was identified for this variant, so PS4 cannot be applied.	cspec PMID:25099575 PMID:28779002 clinvar
BA1	Not met	The highest observed gnomAD v4.1 population frequency is 0.00008%, which is far below the PALB2 BA1 threshold of greater than 0.1%, so BA1 is not met.	gnomad_v4 cspec
PP1	Not assessed	No family cosegregation data, LOD score, or likelihood ratio were identified for this variant, so the PALB2 PP1 thresholds cannot be evaluated.	cspec
PVS1	Met	This variant is a nonsense change predicted to introduce a premature stop codon early in PALB2. PALB2 loss of function is an established disease mechanism in the PALB2 specification, and the available evidence supports applying PVS1 at very strong strength for this truncating variant. SpliceAI shows no significant alternate splice effect prediction (max delta score 0.01), so there is no computational evidence suggesting a different primary mechanism.	cspec pvs1_gene_context pvs1_variant_assessment spliceai PMID:17200671 PMID:25099575 PMID:28779002
BP7	N/A	BP7 is intended for synonymous or deep intronic variants and does not apply to this nonsense coding change.	cspec pvs1_variant_assessment
BP4	Not met	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 BP4 splice threshold of 0.1. However, this variant still creates a premature termination codon, so the lack of predicted splice disruption does not provide benign evidence against the truncating effect. REVEL was unavailable, HCI prior is not available for PALB2, and the BayesDel score was 0.63, but these do not establish a benign interpretation for this nonsense variant.	spliceai bayesdel cspec
BP2	N/A	BP2 is not used in the PALB2 specification.	cspec
PP2	N/A	PP2 is not used for PALB2 because missense variation is not an established disease mechanism in this specification, and this variant is not missense.	cspec pvs1_variant_assessment
PS3	N/A	PS3 is not used for PALB2 in this specification for the present variant context.	cspec
BP3	N/A	BP3 is not used for PALB2 because this specification does not recognize a qualifying repetitive benign region for this gene, and this variant is not an in-frame indel.	cspec pvs1_variant_assessment
PP5	Met	Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.	cspec clinvar
PP3	Not met	SpliceAI predicts no significant splice impact for this variant (max delta score 0.01), which is below the PALB2 PP3 splice threshold of 0.2. REVEL was unavailable, HCI prior is not available for PALB2, and the BayesDel score was 0.63, but PALB2 PP3 is not applied to this truncating variant on the basis of missense-oriented predictors.	spliceai bayesdel cspec
PM5	Met	The PALB2 specification allows PM5_Supporting for truncating variants with premature termination codons upstream of p.Tyr1183. This variant introduces p.Gln228Ter, which is upstream of p.Tyr1183, so PM5_Supporting is met.	cspec pvs1_variant_assessment
PS2	N/A	PS2 is not used for PALB2 in this specification.	cspec
PS1	N/A	PALB2 PS1 is reserved for specific splice-table scenarios and is not used for this nonsense variant.	cspec pvs1_variant_assessment

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