BAP1c.1081_1084delLikely pathogenic

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Variant interpretation report

BAP1 c.1081_1084del, p.(Leu361ThrfsTer68)

NM_004656.4:c.1081_1084del NP_004647.1:p.(Leu361ThrfsTer68) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About BAP1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic)
Expert rules: Not recorded
Pipeline record: 30 Jun 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): NM_004656.4:c.1081_1084del is a 4-bp frameshift deletion in exon 11 of 17, predicted to produce NP_004647.1:p.(Leu361ThrfsTer68) with a premature termination codon in exon 12, well upstream of the last exon-exon junction. Nonsense-mediated decay is expected. BAP1 loss of function is an established disease mechanism for BAP1 tumor predisposition syndrome (BAP1-TPDS). Under ClinGen SVI PVS1 recommendations (PMC6185798), a frameshift variant with predicted NMD in a gene where LOF is a known mechanism qualifies for PVS1 at very strong strength.
PM2 (moderate): NM_004656.4:c.1081_1084del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0.0 in all population databases queried. Under generic ACMG/AMP rules, absence from large population cohorts meets PM2 at moderate strength.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

NM_004656.4:c.1081_1084del is a 4-bp frameshift deletion in exon 11 of 17, predicted to produce NP_004647.1:p.(Leu361ThrfsTer68) with a premature termination codon in exon 12, well upstream of the last exon-exon junction. Nonsense-mediated decay is expected. BAP1 loss of function is an established disease mechanism for BAP1 tumor predisposition syndrome (BAP1-TPDS). Under ClinGen SVI PVS1 recommendations (PMC6185798), a frameshift variant with predicted NMD in a gene where LOF is a known mechanism qualifies for PVS1 at very strong strength.

PM2Moderate

PM2 · moderate

NM_004656.4:c.1081_1084del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0.0 in all population databases queried. Under generic ACMG/AMP rules, absence from large population cohorts meets PM2 at moderate strength.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.090 maximum delta

Recorded SpliceAI maximum delta score: 0.090. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 5 not met · 13 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_004656.4:c.1081_1084del (p.Leu361ThrfsTer68) is a frameshift deletion in exon 11 of BAP1, predicted to cause nonsense-mediated decay and loss of protein function. BAP1 loss of function is an established mechanism for BAP1 tumor predisposition syndrome.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting its rarity in the general population.

This variant is absent from ClinVar and has not been previously reported in the literature with variant-specific evidence.

SpliceAI predicts no significant splicing impact (max delta 0.09), and in silico missense predictors are not applicable to this deletion variant.

No variant-specific functional studies, segregation data, or de novo observations were identified. Two BAP1-focused publications (PMID:18757409, PMID:21874000) were reviewed in full text; neither mentions NM_004656.4:c.1081_1084delCTAG.

Met · 2

PVS1 Very strongNM_004656.4:c.1081_1084del is a 4-bp frameshift deletion in exon 11 of 17, predicted to produce NP_004647.1:p.(Leu361ThrfsTer68) with a premature termination codon in exon 12, well upstream of the last exon-exon junction. Nonsense-mediated decay is expected. BAP1 loss of function is an established disease mechanism for BAP1 tumor predisposition syndrome (BAP1-TPDS). Under ClinGen SVI PVS1 recommendations (PMC6185798), a frameshift variant with predicted NMD in a gene where LOF is a known mechanism qualifies for PVS1 at very strong strength. Details ▾Hide ▴

Evidence considered

Frameshift deletion c.1081_1084del in exon 11/17
PTC in exon 12
Predicted NMD-competent: PTC occurs before last exon-exon junction
BAP1 LOF is established germline disease mechanism (BAP1-TPDS)
Transcript NM_004656.4 is MANE Select

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 ModerateNM_004656.4:c.1081_1084del is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), with allele frequency of 0.0 in all population databases queried. Under generic ACMG/AMP rules, absence from large population cohorts meets PM2 at moderate strength. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (AF=0)
Absent from gnomAD v4.1 (AF=0)
Absent from gnomAD-Canada v1.0 (AF=0)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 5 · evaluated, threshold not reached

PM1 This variant does not lie within a statistically significant mutational hotspot (CancerHotspots.org) and is not located within a well-characterized functional domain without benign variation per available evidence. Details ▾Hide ▴

Evidence considered

CancerHotspots analysis: no significant hotspot at this residue
gnomAD: no population data available for domain-level constraint assessment

PP3 SpliceAI predicts no significant splice impact (max delta score = 0.09), which is below the commonly applied pathogenic threshold of 0.2. REVEL and BayesDel scores are not applicable for deletion variants. No HCI prior probability score is available. Insufficient in silico evidence to support a deleterious effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.09 (below pathogenic threshold of 0.2)
REVEL/BayesDel not available for indels
HCI prior not available for BAP1

Still missing

No in silico missense predictors applicable to this deletion

Sources

spliceai ↗

BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency of 0.0 does not reach the BA1 threshold (>1%). Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0
gnomAD v4.1: AF=0
gnomAD-Canada: AF=0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 The variant is absent from all population databases queried. Allele frequency of 0.0 does not reach the BS1 threshold (>0.3% under generic ACMG rules). Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0
gnomAD v4.1: AF=0
gnomAD-Canada: AF=0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BP4 SpliceAI max delta score of 0.09 is low but does not constitute multiple lines of computational evidence suggesting no impact on gene product. The score is insufficient to meet BP4, which requires strong benign computational predictions. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.09 (insufficient for strong benign call)

Sources

spliceai ↗

Not assessed · 13 · no assessment recorded

PS2 No de novo data with confirmed paternity/maternity are available for this variant. Details ▾Hide ▴

Still missing

No de novo observation data available

PS3 No variant-specific functional studies were identified for NM_004656.4:c.1081_1084delCTAG. Two publications (PMID:18757409, PMID:21874000) were reviewed in full text; neither mentions this variant. OncoKB annotation of Likely Oncogenic/Likely Loss-of-function reflects somatic curation and does not constitute independent germline functional evidence sufficient for PS3. Details ▾Hide ▴

Evidence considered

OncoKB: Likely Oncogenic
Likely Loss-of-function (somatic curation only)
PMID:18757409 and PMID:21874000 reviewed
variant not mentioned

Still missing

No variant-specific functional studies identified

PS4 No case-control prevalence data are available for this variant. Details ▾Hide ▴

Still missing

No affected vs. control prevalence data

PM6 No reported de novo observation (with or without confirmed paternity/maternity) for this variant. Details ▾Hide ▴

Still missing

No de novo observation data

PP1 No cosegregation data are available for this variant. Details ▾Hide ▴

Still missing

No segregation data in affected families

PP4 No patient phenotype or family history data are available for assessment. Details ▾Hide ▴

Still missing

No patient-specific phenotype data

PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic with unavailable evidence. Details ▾Hide ▴

Evidence considered

ClinVar: variant not present

Sources

clinvar ↗

BS2 No data are available regarding observation of this variant in healthy adults with full penetrance expected at an early age. Details ▾Hide ▴

Still missing

No healthy adult carrier data

BS3 No functional studies demonstrating no damaging effect for this variant are available. Details ▾Hide ▴

Still missing

No functional evidence of benign effect

BS4 No segregation data in affected families are available to assess lack of cosegregation. Details ▾Hide ▴

Still missing

No segregation data

BP2 No data are available regarding observation of this variant in trans with a pathogenic variant in a recessive disorder. Details ▾Hide ▴

Still missing

No trans-phase observation data

BP5 No data are available showing this variant in a case with an established alternate molecular basis for disease. Details ▾Hide ▴

Still missing

No alternate molecular basis data

BP6 This variant is absent from ClinVar; no reputable source has reported it as benign with unavailable evidence. Details ▾Hide ▴

Evidence considered

ClinVar: variant not present

Sources

clinvar ↗

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to missense variants with a same-amino-acid change as a known pathogenic variant. This is a frameshift deletion, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions in a non-repeat region or stop-loss variants. This variant is an out-of-frame (frameshift) deletion; the predicted protein effect is already captured under PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to a novel missense change at the same amino acid residue as a previously established pathogenic missense variant. This is a frameshift deletion, not a missense substitution, and no structurally comparable comparator variants were identified (see pm5_candidates.json). Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This is a frameshift deletion, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary disease mechanism. This is a truncating (frameshift) variant, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is an out-of-frame (frameshift) deletion, not an in-frame change. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 applies when a variant is found in a case with an established alternate molecular basis for disease. No such data are available, and PS5 is only applicable when an alternative explanation is documented. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: BAP1
Transcript: NM_004656.4
Coding (HGVS c.): NM_004656.4:c.1081_1084del
Protein (HGVS p.): NP_004647.1:p.(Leu361ThrfsTer68)
GRCh38: chr3:52405141 TCTAG>T
GRCh37: chr3:52439157 TCTAG>T

Gene diagram

Every interpreted variant in BAP1, mapped onto the exon structure of NM_004656.4. Select a row to find it on the plot.

BAP1NM_004656.4

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in BAP1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +289 bp

0.090

SpliceAI acceptor gainat +144 bp

0.000

SpliceAI donor lossat -31 bp

0.080

SpliceAI donor gainat +212 bp

0.000

Pangolin splice lossmagnitude shown

-0.350

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.09 (below pathogenic threshold of 0.2)
REVEL/BayesDel not available for indels
HCI prior not available for BAP1

Still missing

No in silico missense predictors applicable to this deletion

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.09 (insufficient for strong benign call)

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization.

Characterizes BAP1 as a tumor suppressor requiring deubiquitinating activity and nuclear localization, demonstrating tumor suppression in lung cancer xenograft models. NM_004656.4:c.1081_1084delCTAG was not identified in this paper.
Does not name this variant
PMID 18757409 ↗
Germline BAP1 mutations predispose to malignant mesothelioma.

Reports discovery of germline BAP1 mutations (intron 6 splice acceptor, c.1832delC, c.2008-2011delTCAC, p.Gln684X) in families with mesothelioma and uveal melanoma, establishing BAP1-related cancer syndrome. NM_004656.4:c.1081_1084delCTAG was not identified among the variants reported.
Does not name this variant
PMID 21874000 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.090 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.