Variant classification summary

NM_004656.4:c.376_382delAGCAAAG

BAP1 · NP_004647.1:p.(Ser126AspfsTer59) · NM_004656.4

GRCh37: chr3:52441469 CCTTTGCT>C · GRCh38: chr3:52407453 CCTTTGCT>C

Gene: BAP1 Transcript: NM_004656.4

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

BAP1

Transcript

NM_004656.4

Protein

NP_004647.1:p.(Ser126AspfsTer59)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (very strong): NM_004656.4:c.376_382del is a frameshift deletion in BAP1 exon 6, creating a premature termination codon at p.S126Dfs*59 with predicted NMD. BAP1 loss-of-function is the established germline disease mechanism for BAP1 tumor predisposition syndrome (PMID:35051358, PMID:35348477, PMID:39842618). NM_004656.4 is the MANE Select transcript.

2

PM2 (supporting): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with a rare pathogenic variant.

3

Classification: Likely Pathogenic. Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): PVS1 (Very Strong) is met and PM2 (Supporting) is met. This combination of 1 Very Strong and 1 Supporting criterion does not satisfy the formal threshold for Pathogenic (which requires 1 Very Strong + ≥2 Supporting or ≥1 Strong). However, a frameshift null variant in a gene with established LoF disease mechanism, absent from all population databases, is classified as Likely Pathogenic per clinical practice. Per ACMG/AMP 2015, the evidence falls between formal Likely Pathogenic and Pathogenic thresholds; classification is Likely Pathogenic with a note that additional supporting evidence would elevate to Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Met	Frameshift variant NM_004656.4:c.376_382del (p.S126Dfs*59) in BAP1 exon 6 creates a premature termination codon at residue 184 of 730, well upstream of the NMD escape boundary. BAP1 has an established loss-of-function disease mechanism (BAP1 tumor predisposition syndrome). NM_004656.4 is the MANE Select transcript. Under PMC6185798, a frameshift in a gene with confirmed germline LoF mechanism qualifies for PVS1 at full strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to same amino acid change via different nucleotide change. This is a 7bp frameshift deletion, not a nucleotide substitution at a known pathogenic missense site.
PS2	Not assessed	No de novo data available for this variant. No case reports with parental testing were identified.
PS3	Not assessed	No variant-specific functional studies identified. Two publications (PMID:18757409, PMID:21874000) discuss BAP1 tumor suppressor function at the gene level but neither mentions NM_004656.4:c.376_382del or the resulting protein change p.S126Dfs*59.
PS4	Not assessed	Variant is absent from ClinVar and no case reports with this specific variant were identified in the literature reviewed.
PS5	Not assessed	Variant is absent from ClinVar; no expert panel classification available.
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot in BAP1.
PM2	Met	This variant is absent from gnomAD v2.1 and v4.1 population databases, meeting the non-VCEP PM2 threshold of allele frequency below 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions or insertions in non-repeat regions. This variant is a 7bp frameshift deletion, which is assessed under PVS1 rather than PM4.
PM5	N/A	PM5 evaluates a novel missense change at the same residue as a known pathogenic missense variant. This is a frameshift deletion, not a missense variant, and the residue-level comparator semantics are not applicable.
PM6	Not assessed	No de novo observations reported for this variant. PM6 requires a confirmed de novo event in a patient without family history.
PP1	Not assessed	No segregation data available for this variant.
PP2	N/A	PP2 applies to genes where missense variants are a common disease mechanism. BAP1 disease is driven by loss-of-function variants, and HCI prior data is not available for this gene.
PP3	Not met	Per PMC6185798, splice prediction scores are not stacked with PVS1 for the same variant. REVEL and BayesDel are not applicable to this frameshift deletion. Although SpliceAI predicts acceptor loss (DS_AL=1.0, DS_AG=0.99), this overlaps with the PVS1 evidence of a null variant effect.	spliceai pvs1_generic_framework
PP4	Not assessed	No patient phenotype data provided for this specific variant assessment.
PP5	Not assessed	Variant is absent from ClinVar; no expert panel classification available to support PP5.
BA1	N/A	BA1 requires allele frequency above 1% in population databases. This variant is absent from gnomAD.
BS1	N/A	BS1 requires allele frequency above 0.3% in population databases. This variant is absent from gnomAD.
BS2	Not assessed	No data on observation of this variant in healthy adults. Absence from gnomAD does not constitute BS2 evidence.
BS3	Not assessed	No variant-specific functional studies demonstrating a benign effect were identified. The two publications reviewed discuss BAP1 tumor suppressor function at gene level only.
BS4	Not assessed	No segregation data available for assessing lack of cosegregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This variant itself is a truncating frameshift, not a missense variant.
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic variant in BAP1.
BP3	N/A	BP3 applies to in-frame deletions in repetitive regions. This is a frameshift deletion.
BP4	Not met	No in silico evidence supporting a benign effect. SpliceAI predicts acceptor loss (max delta 1.0). REVEL and BayesDel are not applicable to this frameshift variant.	spliceai
BP5	Not assessed	No data on an alternative molecular basis for disease in affected individuals carrying this variant.
BP6	Not assessed	No reputable source has classified this variant as benign. Variant is absent from ClinVar.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion.

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