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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.SMARCA4 encodes a protein that uses energy from ATP to remodel chromatin, helping control which genes are turned on and supporting DNA replication and repair. It is associated with rhabdoid tumor predisposition syndrome and inherited susceptibility to certain childhood brain tumors and ovarian cancer. SMARCA4 acts as a tumor-suppressor gene and is commonly altered in several cancers, including malignant rhabdoid tumors, lymphoma, medulloblastoma, and lung and ovarian cancers.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at very strong: nonsense c.3067G>T creates p.Glu1023Ter in exon 21 of a 1680-residue protein, with downstream coding exons supporting nonsense-mediated decay.
Met, supporting: the variant is absent from gnomAD v2.1 and v4.1, giving observed frequency 0 versus the PM2 threshold of <=0.0001.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) satisfy the generic ACMG/AMP fallback combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1 allele counts were not recorded for this variant.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.003. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not 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.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 3 not met · 13 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No applicable SMARCA4-specific VCEP or CSPEC framework was retrieved; generic ACMG criteria were used only where relevant.
The available evidence supports neither exact-variant phenotype prevalence assessment nor exact-variant ClinVar expert-panel PP5/BP6 assessment.
No governing SMARCA4 VCEP or CSPEC framework was available, so the supplied generic ACMG/AMP population thresholds were used.
The variant is absent from the available gnomAD all-comers datasets and from the reported non-cancer subset entries; this supports PM2 at supporting strength but provides no positive evidence for BA1, BS1, or BS2.
No criteria match.
No SMARCA4-specific VCEP or CSPEC framework was available, so the generic ClinGen SVI PVS1 framework (PMC6185798) applies. NM_001128849.1:c.3067G>T is a nonsense variant predicted to produce NP_001122321.1:p.(Glu1023Ter), truncating the 1680-amino-acid protein after residue 1022 and removing 657 amino acids. VariantValidator places it in exon 21, which is followed by additional coding exons; therefore the premature termination is not in the terminal exon and is expected to be subject to nonsense-mediated decay rather than escape it. The transcript is RefSeq transcript variant 1 and RefSeq Select for SMARCA4, supporting transcript relevance. The truncation occurs well before the normal C terminus and no evidence indicates a non-critical distal exon, a repeat-region exception, or enrichment for benign loss-of-function variation in the affected exon. SMARCA4 loss of function is supported as a germline disease mechanism. No named SVI or VCEP downgrade rule applies, so PVS1 remains at full strength.
Generic ClinGen SVI PVS1 framework (PMC6185798); nonsense variant with expected NMD and no applicable downgrade.
PM2 is met at supporting strength. NM_001128849.1:c.3067G>T (p.Glu1023Ter) is absent from gnomAD v2.1 and gnomAD v4.1. The case data additionally report absence from the gnomAD v2.1 non-cancer exome subset and gnomAD v3.1 non-cancer genome subset. Under the generic ClinGen SVI calibration supplied for this case, PM2 supporting applies at allele frequency <=0.0001; an absent variant has observed frequency 0 and satisfies that threshold. No governing VCEP specification was available.
Generic ClinGen SVI PM2 supporting: population allele frequency <=0.0001; absent variant has observed frequency 0 and meets the threshold.
BA1 is not met. NM_001128849.1:c.3067G>T (p.Glu1023Ter) is absent from gnomAD v2.1 and gnomAD v4.1, so its observed allele frequency is 0 and does not reach the generic ACMG/AMP stand-alone benign threshold of >=0.05. The non-cancer gnomAD v2.1 exome and v3.1 genome entries are also reported as absent; no governing VCEP specification was available to replace the generic rule.
Generic ACMG/AMP BA1: observed allele frequency >=0.05; absent variant has frequency 0 and does not meet the threshold.
BS1 is not met. The variant is absent from gnomAD v2.1 and gnomAD v4.1, giving no observed population frequency at or above the generic BS1 threshold of >=0.01. The non-cancer gnomAD v2.1 exome and v3.1 genome entries are likewise absent, and no gene-specific frequency threshold or VCEP specification was available.
Generic BS1: population allele frequency >=0.01; absent variant has frequency 0 and does not meet the threshold.
BS2 is not met. The available population evidence reports the variant absent from gnomAD v2.1 and v4.1, including the reported non-cancer subsets, and therefore provides no observation of the variant in healthy adults, unaffected individuals, or healthy homozygotes. Absence is not positive BS2 evidence; no independent healthy-carrier or homozygote observation was supplied.
BS2 requires observation of the variant in healthy adults or unaffected individuals, typically including healthy homozygotes where relevant; absence from population databases does not satisfy BS2.
No proband-level de novo observation is documented for NM_001128849.1:c.3067G>T (SMARCA4 p.Glu1023Ter), and no confirmed maternity/paternity or parental testing results are provided. Therefore, the generic ACMG/AMP PS2 requirement for an apparently de novo variant with appropriate parental confirmation cannot be evaluated.
Generic ACMG/AMP PS2: de novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed; stronger application requires appropriate phenotype and reliable parental testing.
No reviewed publication reports a validated functional assay performed on SMARCA4 NM_001128849.1:c.3067G>T (p.Glu1023Ter). The papers describe SMARCA4 loss-of-function biology, truncating variants, tumor cohorts, protein loss, or generic BRG1 function, but none directly tests this variant with appropriate controls and a disease-relevant assay. Therefore, the generic ACMG/AMP PS3 criterion cannot be applied from the available evidence, and no PS3 strength is assigned.
Generic ACMG/AMP PS3: apply only when well-established functional studies provide valid evidence that the variant damages gene or gene-product function; no strength is assigned without variant-specific assay evidence.
No case-control dataset, affected-case count for NM_001128849.1:c.3067G>T, control count, odds ratio, or other enrichment statistic is available. The literature extracts describe SMARCA4 alterations in disease cohorts but do not mention this exact variant and do not establish variant-level case-control enrichment; therefore PS4 cannot be assessed.
{'source': 'generic_acmg_combination_rules', 'criterion': 'PS4 requires prevalence or enrichment of the variant in affected individuals compared with controls; no criterion-specific numeric threshold is available here.'}
No affected-proband observations are provided for NM_001128849.1:c.3067G>T, and the case contains no evidence establishing a second pathogenic SMARCA4 variant in trans, phase, or a recessive inheritance context. Therefore, PM3 cannot be assessed from the available evidence.
PM3 requires the variant to be observed in trans with a pathogenic variant in an affected individual with a recessive disorder; without affected-proband and phase evidence, PM3 is not assessed.
No unconfirmed de novo observation is documented for NM_001128849.1:c.3067G>T (SMARCA4 p.Glu1023Ter). The available case materials do not identify an affected proband, phenotype, parental testing, or a credible report of the variant arising de novo without confirmed maternity and paternity; PM6 therefore cannot be evaluated.
Generic ACMG/AMP PM6: assumed de novo, but without confirmation of paternity and maternity, in a patient with the disease and no family history; phenotype should be consistent with the disease.
No family segregation data are provided for NM_001128849.1:c.3067G>T (SMARCA4 p.Glu1023Ter). The available materials do not report affected or unaffected relatives, informative meioses, variant status in relatives, or a phenotype pattern that would permit assessment of cosegregation or strength escalation.
Generic ACMG/AMP PP1: cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease; strength depends on the amount and informativeness of segregation evidence.
No patient phenotype, clinical diagnosis, disease-specific presentation, or phenotype-to-gene fit is provided for this variant. General SMARCA4 disease literature cannot substitute for the affected individual's highly specific phenotype, so PP4 cannot be assessed.
{'source': 'generic_acmg_combination_rules', 'criterion': "PP4 requires a patient's phenotype or family history highly specific for a disease with a single-gene etiology; no patient phenotype is available."}
ClinVar contains no exact-variant record for NM_001128849.1:c.3067G>T, no variation ID, and no review status or expert-panel classification. Because an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is required, PP5 cannot be assessed and is not triggered by the available OncoKB label or literature.
{'source': 'generic_acmg_combination_rules', 'criterion': 'Apply PP5 only when an exact-variant ClinVar expert-panel classification is Pathogenic or Likely pathogenic; ordinary submissions, aggregate labels, and non-expert assertions are excluded.'}
No reviewed publication reports a validated functional assay demonstrating that SMARCA4 NM_001128849.1:c.3067G>T (p.Glu1023Ter) retains normal function. The available studies concern general SMARCA4 biology, other truncating variants, tumor-level protein expression, or non-variant-specific experiments and therefore cannot establish a benign functional effect for this variant. Consequently, the generic ACMG/AMP BS3 criterion is not assessable and no BS3 strength is assigned.
Generic ACMG/AMP BS3: apply only when well-established functional studies show no damaging effect on protein function or a relevant biological process; no strength is assigned without variant-specific assay evidence.
No family data are provided to show that NM_001128849.1:c.3067G>T (SMARCA4 p.Glu1023Ter) fails to segregate with disease. There are no documented unaffected carriers, informative non-segregating meioses, reliable phenotypic assessments, or family structure from which a meaningful non-segregation conclusion can be drawn.
Generic ACMG/AMP BS4: lack of segregation in affected members of a family; application requires reliable family phenotyping and informative variant testing, while age-dependent disease must be considered.
No case, family, tumor-normal, or segregation evidence shows NM_001128849.1:c.3067G>T in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant. Therefore, BP2 cannot be assessed from the available evidence.
BP2 requires observation of the variant in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant; absent phase and qualifying observation data, BP2 is not assessed.
No evidence shows that this patient has a confirmed alternative molecular explanation for the relevant disease phenotype, and no governing VCEP-specific BP5 rule or numeric threshold is available. The absence of phenotype and alternative molecular-diagnosis data leaves BP5 not assessed.
{'source': 'generic_acmg_combination_rules', 'criterion': "BP5 requires a documented alternative molecular explanation for the patient's phenotype; no such patient-level evidence is available."}
ClinVar contains no exact-variant record for NM_001128849.1:c.3067G>T, no variation ID, and no review status or expert-panel classification. Because an exact-variant ClinVar expert-panel Benign or Likely benign classification is required, BP6 cannot be assessed and is not triggered by the absence of ClinVar data or by non-expert sources.
{'source': 'generic_acmg_combination_rules', 'criterion': 'Apply BP6 only when an exact-variant ClinVar expert-panel classification is Benign or Likely benign; ordinary submissions, aggregate labels, and non-expert assertions are excluded.'}
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
PP3 is not applicable because NM_001128849.1:c.3067G>T is a nonsense variant, predicting p.(Glu1023Ter), rather than a missense or splice-region/intronic variant within the calibrated scope of PP3. SpliceAI, REVEL, and BayesDel were therefore not evaluated for this criterion.
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_repeat_region_indel
BP4 is not applicable because NM_001128849.1:c.3067G>T is a nonsense variant, predicting p.(Glu1023Ter), rather than a missense or splice-region/intronic variant within the calibrated scope of BP4. SpliceAI, REVEL, and BayesDel were therefore not evaluated for this criterion.
deterministic_prefilter: requires_synonymous
Every interpreted variant in SMARCA4, mapped onto the exon structure of NM_001128849.1. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
PP3 is not applicable because NM_001128849.1:c.3067G>T is a nonsense variant, predicting p.(Glu1023Ter), rather than a missense or splice-region/intronic variant within the calibrated scope of PP3. SpliceAI, REVEL, and BayesDel were therefore not evaluated for this criterion.
BP4 is not applicable because NM_001128849.1:c.3067G>T is a nonsense variant, predicting p.(Glu1023Ter), rather than a missense or splice-region/intronic variant within the calibrated scope of BP4. SpliceAI, REVEL, and BayesDel were therefore not evaluated for this criterion.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.
5 paper records listed. 2 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
The majority of the mutations affected the ATPase domain and are expected to result in truncated proteins (Fig. 1a).
Location Results, paragraph describing sequencing of 12 SCCOHT cases and BIN-67 cells
Context Whole-genome and whole-exome sequencing of tumors, matched germline samples, and the BIN-67 SCCOHT cell line; SMARCA4 mutations were validated by Sanger sequencing, and SMARCA4 protein expression was assessed by immunohistochemistry and protein blotting.
Nearly all mutations are predicted to truncate the protein and are scattered along the gene, as one would expect for a tumor suppressor gene.
Location Figure 1 legend; Results and Discussion sections
Context Whole-exome sequencing, Sanger sequencing, SMARCA4 immunohistochemistry, fluorescence in situ hybridization, and analysis of germline and tumor samples from familial and non-familial SCCOHT cases.
The BRG1 (or hBRM) protein is the central catalytic ATPase of the SWI/SNF chromatin-remodeling complex.
History
Sequencing of all protein-coding exons in 279 cancer-related genes for 12 paired tumor and normal SCCOHT samples identified inactivating biallelic SMARCA4 mutations in each case.
Results, paragraph 3; Functional studies
SMARCA4 mutations resulting in loss of SMARCA4 protein expression were identified in eight tumors. One additional tumor showed retained (normal) SMARCA4 protein expression. ... Sequencing of SMARCA4 and FISH analysis were carried out as described previously [14] and revealed nonsense SMARCA4 mutations in six cases
Results, paragraph 1, p. 454; Table 1; Results, paragraph 2, p. 454
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The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
Absent from gnomAD v4.1.
Absent from gnomAD v2.1.
Not available in gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.