NM_024675.4:c.2631G>C

PALB2 · NP_078951.2:p.(Trp877Cys) · NM_024675.4

GRCh37: chr16:23637674 C>G · GRCh38: chr16:23626353 C>G

Gene: PALB2 Transcript: NM_024675.4

Final call

VUS

BP1_Supporting

Variant details

Gene

PALB2

Transcript

NM_024675.4

Protein

NP_078951.2:p.(Trp877Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The PALB2 c.2631G>C (p.Trp877Cys, p.W877C) variant has not been observed in COSMIC and has been reported in ClinVar as likely benign by a single clinical laboratory.

In population data, this variant is absent from gnomAD v2.1 and present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), with a highest observed South Asian frequency of 1/91,090 alleles (0.00110%), which is below the PALB2 BS1 and BA1 thresholds but above the PALB2 PM2 under-represented subpopulation exception threshold for a singleton observation.

In silico splice prediction does not support a clinically significant splice effect, with a SpliceAI maximum delta score of 0.17, which is below the PALB2 PP3 threshold of 0.2.

Final determination: No criteria-combination rule matched the adjudicated criteria in the Richards et.al., 2015 - Combining rules v1.2.0 framework, so the variant remains a Variant of Uncertain Significance pending human review.

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 quantitative segregation data or Bayes factor data were identified for this variant, so the PALB2 BS4 thresholds cannot be evaluated.	cspec
PM4	N/A	This is a missense substitution, not an in-frame insertion/deletion or stop-loss variant, and PALB2 VCEP marks PM4 as not applicable for this context.	cspec
PM3	Not assessed	No Fanconi anemia proband data or phase-confirmed trans observations with a pathogenic PALB2 variant were identified, so PM3 cannot be assigned.	cspec
BP6	N/A	BP6 is not used by the PALB2 VCEP.	cspec
BP5	N/A	BP5 is not applied in the PALB2 VCEP framework because co-occurrence with other pathogenic variants is not considered sufficiently informative for PALB2.	cspec
BP1	Met	This missense variant changes PALB2 p.Trp877 to cysteine. The PALB2 VCEP applies BP1 to all missense variants because truncating variants are the predominant established disease mechanism and pathogenic missense variants are thought to be exceedingly rare.	cspec
BS3	N/A	BS3 is not applied by the PALB2 VCEP for this missense variant framework, and no validated benign functional assay evidence was identified.	cspec
BS2	Not assessed	No data were identified showing this variant in informative unaffected individuals under the PALB2 Fanconi anemia BS2 scoring framework, so BS2 cannot be evaluated.	cspec
BS1	Not met	This variant is present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), with a highest observed population frequency of 1/91,090 alleles in South Asian individuals (0.00110%). These values are below the PALB2 BS1 threshold of >0.01%, so BS1 is not met.	gnomad_v4 cspec
PP4	N/A	PP4 is not applied in the PALB2 VCEP framework because PALB2-related cancer predisposition does not have a sufficiently specific phenotype for this criterion.	cspec
PM6	N/A	PM6 is not applied by the PALB2 VCEP.	cspec
PM2	Not met	This variant is absent from gnomAD v2.1 and is present in gnomAD v4.1 at 1/1,614,170 alleles (0.00006%), which is below the PALB2 PM2_Supporting threshold of ≤ 0.000333%. However, the highest observed frequency is a single South Asian allele at 1/91,090 (0.00110%), which exceeds the PALB2 under-represented subpopulation exception threshold, so PM2_Supporting is not applied.	gnomad_v2 gnomad_v4 cspec
PM1	N/A	PM1 is not used for PALB2 because missense pathogenic variation has not been confirmed as a disease mechanism, and no statistically significant hotspot was identified for this residue.	cspec hotspots
PS4	Not met	No PALB2 case-control data were identified showing a significant enrichment of this variant in affected individuals, and ClinVar contains only a single likely benign submitter. Therefore the PALB2 PS4 threshold is not met.	clinvar cspec
BA1	Not met	This variant is present in gnomAD v4.1 at 0.00006% overall and 0.00110% in the highest observed population, both of which are below the PALB2 BA1 threshold of >0.1%. BA1 is not met.	gnomad_v4 cspec
PP1	Not assessed	No segregation data with affected relatives, LOD score, or Bayes factor were identified for this variant, so PP1 cannot be assessed.	cspec
PVS1	Not met	Germline loss of function is an established disease mechanism for PALB2, but this variant is a missense substitution p.(Trp877Cys) and does not fall into the PALB2 or generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice variants. PVS1 is therefore not applied.	cspec pvs1_gene_context pvs1_variant_assessment
BP7	N/A	BP7 is intended for synonymous or qualifying deep intronic variants, whereas this variant is a missense substitution.	cspec
BP4	N/A	Although SpliceAI predicts a low splice effect with a maximum delta score of 0.17, the PALB2 VCEP does not apply BP4 for missense variants. BP4 is therefore not used.	spliceai cspec
BP2	N/A	BP2 is not applied in the PALB2 VCEP framework.	cspec
PP2	N/A	PP2 is not used for PALB2 because missense variants are not an established disease mechanism in this framework.	cspec
PS3	N/A	PS3 is not applied by the PALB2 VCEP for this context, and no validated damaging functional assay evidence was identified for this variant.	cspec
BP3	N/A	This is not an in-frame insertion or deletion in a repetitive region, and BP3 is not applicable in the PALB2 VCEP framework.	cspec
PP5	N/A	PP5 is not used by the PALB2 VCEP.	cspec
PP3	Not met	SpliceAI shows a maximum delta score of 0.17 for this missense variant, which is below the PALB2 PP3 splicing threshold of ≥ 0.2. PP3 is not met.	spliceai cspec
PM5	N/A	PM5_Supporting in PALB2 is restricted to truncating or qualifying splice variants upstream of p.Tyr1183 and is not used for missense changes, so PM5 does not apply to p.(Trp877Cys).	cspec
PS2	N/A	PS2 is not applied by the PALB2 VCEP for PALB2-related cancer predisposition.	cspec
PS1	N/A	The PALB2 VCEP does not use PS1 for missense substitutions, and no PALB2 PS1 splicing-table evidence was identified for this variant.	cspec spliceai

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