Classification rationale

PM2 VUS

BAP1 c.126T>C

PM2 (Supporting): gnomAD v4.1 total AF 3.10757e-06 (5/1,608,972 alleles) with zero homozygotes, absent from gnomAD v2.1, more than 30-fold below the 0.1% pathogenic-support threshold. Variant of Uncertain Significance: the single supporting pathogenic criterion (PM2) satisfies no ACMG/AMP 2015 Pathogenic or Benign combination threshold.

PM2 → VUS

Gene diagram · NM_004656.4 · variants mapped to exon structure

BAP1 NM_004656.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 18 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): present in gnomAD v4.1 at total AF 3.10757e-06 (5/1,608,972 alleles) and absent from gnomAD v2.1, more than 30-fold below the 0.1% threshold.

gnomAD v4.1 (gnomad_v4): total AF 3.10757e-06 (0.00031%; 5/1,608,972 alleles), exome AF 2.74589e-06, genome AF 6.56806e-06, grpmax FAF 4.43e-06, 0 homozygotes; highest subpopulation AF 2.66987e-05 (AFR, 0.00267%)gnomAD v2.1 (gnomad_v2): variant absentPM2 per ACMG/AMP 2015 (PMID 25741868): absent in controls or at extremely low frequency; pipeline non-VCEP operating threshold PM2 < 0.1% — all observed frequencies are >30-fold below the threshold

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 Not assessed: no de novo occurrence or parental testing for this variant is reported in any ClinVar submission or publication.

PS3 Not assessed: no functional assay evidence for this variant was available in any source.

PS4 Not assessed: no case-control or cohort prevalence data for this variant exists; only population frequencies were available.

PM6 Not assessed: no de novo occurrence of this variant is reported in any source, with or without confirmed parentage.

PP1 Not assessed: no co-segregation data in affected family members exists for this variant in any ClinVar submission or publication.

PP3 Not met: SpliceAI max delta score 0.01 versus the 0.2 recommended splice-impact threshold, and no other predictor indicates a deleterious effect.

PP4 Not assessed: no proband phenotype or family history data was available to evaluate phenotype specificity.

PP5 Not met: the ClinVar record has zero expert-panel submissions, so no expert-panel Pathogenic/Likely pathogenic classification exists for this variant.

Benign

BA1 Not met: highest observed allele frequency 0.00267% (African/African American) versus the 1% stand-alone benign threshold.

BS1 Not met: maximum allele frequency 0.00267% versus the 0.3% threshold for this rare dominant cancer predisposition syndrome.

BS2 Not met: gnomAD v4.1 reports zero homozygotes (0/1,608,972 alleles) and no healthy-adult enrichment was observed.

BS3 Not assessed: no well-established functional study of this variant was available; the SpliceAI prediction is in-silico, not a functional assay.

BS4 Not assessed: no family segregation data of any kind exists to evaluate non-segregation.

BP2 Not met: no source reports this variant in trans or cis with a pathogenic variant.

BP4 Not met: only one line of computational evidence is available (SpliceAI delta 0.01), while BP4 requires multiple concordant lines.

BP5 Not assessed: no case-level data exists to identify an alternate molecular basis for disease.

BP6 Not met: the ClinVar record has zero expert-panel submissions, so no expert-panel Benign/Likely benign classification exists for this variant.

BP7 Not assessed: no splice impact is predicted (SpliceAI delta 0.01), but the required nucleotide-conservation data was unavailable.

N/A · 9 PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.10757e-06; MAF= 0.00031%, 5/1608972 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.66987e-05; MAF= 0.00267%, 2/74910 alleles, homozygotes = 0); grpmax FAF= 4.43e-06.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,608,972
0 hom · FAF 0.00044%

African/African American 2 / 74,910	0.0027%
East Asian 1 / 44,822	0.0022%
European (non-Finnish) 2 / 1,177,902	0.00017%

+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 515124)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

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

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

27748099 ↗ BAP1 Tumor Predisposition Syndrome. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR