Classification rationale

PM2 BP4 VUS

SMARCB1 c.787A>G

NM_003073.4:c.787A>G (p.Ile263Val) is a missense variant in exon 6 of SMARCB1. The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (9.29e-06, 15 heterozygotes, 0 homozygotes), meeting PM2 at supporting level.¹ Multiple in silico predictors suggest no significant impact: SpliceAI max delta 0.01, REVEL 0.326, BayesDel -0.137856, meeting BP4 at supporting_benign level.² This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories.³ No functional studies, segregation data, de novo observations, or case-control data are available for this variant. With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced and insufficient to reach a likely pathogenic or likely benign classification.⁴

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 revelbayesdelspliceai ↗

3 clinvar ↗

4 generic_acmg_combination_rules

Gene diagram · NM_003073.4 · variants mapped to exon structure

SMARCB1 NM_003073.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

The variant is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (allele frequency = 9.29e-06, 15/1,613,888 alleles, 0 homozygotes; grpmax FAF = 6.88e-06). This is well below the 0.1% PM2 threshold for generic ACMG/AMP. Absent from gnomAD-Canada.

gnomAD v2.1: absent. gnomAD v4.1: AF = 9.29e-06 (15/1613888 alleles

gnomad_v2 ↗gnomad_v4 ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI max delta score is 0.01 (no predicted splicing impact). REVEL score is 0.326 (below pathogenic threshold of 0.5). BayesDel score is -0.137856 (negative, predicting a benign effect). Three independent in silico predictors concur on no deleterious effect.

SpliceAI max delta: 0.01 (no splice impact). REVEL: 0.326 (below 0.5). BayesDel: -0.137856 (benign prediction).

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No evidence of a different nucleotide change at codon 263 producing the same amino acid substitution (p.Ile263Val) that has been previously classified as pathogenic.

PS2 No de novo observation data available for this variant.

PS3 No variant-specific functional studies identified.

PS4 No case-control data or variant-specific case counts available.

PM1 The variant does not lie in a statistically significant hotspot per the Cancer Hotspots assessment.

PM6 No de novo observation data available for this variant.

PP1 No segregation data available for this variant.

PP2 No gene-level constraint metrics (e.g., Missense Z-score, gnomAD constraint) were retrieved to establish a low rate of benign missense variation in SMARCB1.

PP3 Multiple lines of computational evidence do not support a deleterious effect.

PP4 No patient-specific phenotypic data available for this variant.

PP5 No reputable source has classified this variant as pathogenic.

Benign

BS1 The variant allele frequency in gnomAD v4.1 is 0.00093% (9.29e-06), far below the 0.3% BS1 threshold for generic ACMG/AMP.

BS2 While the variant is observed in gnomAD v4.1 in 15 heterozygous individuals, gnomAD does not provide individual-level phenotype confirmation of healthy adult status.

BS3 No variant-specific functional assays demonstrating no damaging effect are available.

BS4 No family segregation data available for this variant.

BP1 While loss-of-function is an established disease mechanism for SMARCB1, missense variants are also documented as disease-causing in SMARCB1-related disorders (e.g., Coffin-Siris syndrome, schwannomatosis).

BP2 No data on observation in trans with a pathogenic variant in SMARCB1.

BP5 No data on an alternate molecular basis for disease in an individual carrying this variant.

BP6 No reputable source has classified this variant as benign.

N/A · 7 PVS1 · PM3 · PM4 · PM5 · BA1 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.29433e-06; MAF= 0.00093%, 15/1613888 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.59985e-05; MAF= 0.00160%, 1/62506 alleles, homozygotes = 0); grpmax FAF= 6.88e-06.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

This variant is absent from gnomAD-Canada.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00093% · 15 / 1,613,888
0 hom · FAF 0.00069%

Remaining individuals 1 / 62,506	0.0016%
European (non-Finnish) 14 / 1,179,944	0.0012%

+ 8 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 Uncertain significance (2 clinical laboratories). (ClinVarID = 1760986)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.326. BayesDel score = -0.137856.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMARCB1, a protein involved in chromatin remodeling, is inactivated by mutation or deletion in various cancer types including soft tissue sarcomas and

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

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 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

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

Re-run this variant?