NM_001128849.1:c.335C>T (p.Pro112Leu) is a missense variant in SMARCA4 identified in the germline context.1 This variant is present at extremely low frequency in population databases (gnomAD v2.1: 1/31,372 alleles, 0.003%; gnomAD v4.1: 3/1,613,788 alleles, 0.0002%), meeting PM2 at moderate strength.2 No functional studies, case-control data, segregation data, or de novo observations are available for this variant. In silico tools produce conflicting predictions (REVEL 0.609 pathogenic; BayesDel -0.0146 benign). ClinVar classification is Uncertain significance with single-submitter review status.3 Only one moderate criterion (PM2) is met. Under generic ACMG/AMP 2015 combination rules, a single moderate criterion is insufficient to reach Likely pathogenic or Likely benign. The variant is classified as Uncertain significance.4
SMARCA4
Final classification
VUS
SMARCA4 c.335C>T · p.Pro112Leu
SMARCA4
NM_001128849.1:c.335C>T (p.Pro112Leu) is a missense variant in SMARCA4 identified in the germline context.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
SMARCA4 c.335C>T
PM2
→
VUS
4
generic_acmg_combination_rulesPMID:25741868 ↗
Gene diagram
· NM_001128849.1 · variants mapped to exon structure
SMARCA4
NM_001128849.1
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 22 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
This variant is present at extremely low frequency in population databases. gnomAD v2.1 AF=3.19e-05 (0.00319%, 1/31,372 alleles), gnomAD v4.1 AF=1.86e-06 (0.00019%, 3/1,613,788 alleles), both far below the 0.1% PM2 threshold. Absent from gnomAD-Canada. No homozygotes observed. Highest subpopulation frequency is African/African American at 0.0115% (v2.1) and 0.0040% (v4.1).
gnomAD v2.1: 1/31372 alleles (0.0032%)genome only
Assessed · not applied
Pathogenic
PS1
No evidence that the same amino acid change (p.Pro112Leu) has been established as pathogenic via a different nucleotide change.
PS2
No de novo data available.
PS3
No functional studies identified for NM_001128849.1:c.335C>T (p.Pro112Leu).
PS4
No case-control studies or variant-specific case prevalence data available.
PM1
Position 112 in SMARCA4 lies in the N-terminal region outside characterized critical functional domains (QLQ, HSA, BRK, DExx helicase, HELICc, Bromodomain).
PM5
No same-residue pathogenic missense comparator variants identified at Pro112.
PM6
No de novo data available.
PP1
No segregation data available.
PP2
Insufficient constraint data to apply PP2.
PP3
In silico tools produce conflicting predictions.
PP4
Patient phenotype information not available.
PP5
ClinVar classification for this variant is Uncertain significance (3 clinical laboratories) and Likely benign (1 laboratory), all with criteria provided, single submitter review status.
Benign
BA1
gnomAD allele frequency far below BA1 threshold of 1%.
BS1
gnomAD allele frequency far below BS1 threshold of 0.3%.
BS2
Only 4 total allele observations across gnomAD v2+v4 combined (>1.6M alleles).
BS3
No functional studies available showing that this variant has no deleterious effect.
BS4
No segregation data available to demonstrate lack of cosegregation with disease.
BP1
SMARCA4 missense variants are an established disease mechanism.
BP2
No data available on observation of this variant in trans with a known pathogenic variant.
BP4
In silico tools produce conflicting predictions.
BP5
No data available on an alternate molecular basis for disease in this individual.
BP6
ClinVar classification for this variant is Uncertain significance (3 labs) and Likely benign (1 lab), all with single-submitter review status.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85898e-06; MAF= 0.00019%, 3/1613788 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00449e-05; MAF= 0.00400%, 3/74916 alleles, homozygotes = 0); grpmax FAF= 1.063e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.18756e-05; MAF= 0.00319%, 1/31372 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0.000114837; MAF= 0.01148%, 1/8708 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,613,788
0 hom · FAF 0.0011%
0 hom · FAF 0.0011%
African/African American 3 / 74,916 |
0.004% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))
gnomAD v2.1
0.0032%
· 1 / 31,372
0 hom
0 hom
African/African American 1 / 8,708 |
0.011% |
+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 389324)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.609. BayesDel score = -0.0146094.
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. SMARCA4, a tumor suppressor involved in chromatin remodeling, is recurrently altered in small cell carcinoma of the ovaries, hypercalcemic type (SCCOH
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.
Sources & reference links
Triaged references · 3 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
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