0%
ARID1Ac.782C>ALikely pathogenic
Print report
Variant interpretation report

ARID1A c.782C>A, p.(Ser261Ter)

NM_006015.5:c.782C>A NP_006006.3:p.(Ser261Ter) Nonsense · exon 1 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 ARID1A

ARID1A encodes a component of the SWI/SNF chromatin-remodeling complex, which regulates gene expression by altering chromatin structure around target genes. It binds AT-rich DNA sequences and helps recruit the remodeling complex to its targets. Germline mutations in ARID1A cause Coffin-Siris syndrome, a condition marked by developmental delay and coarse facial features. ARID1A also acts as a tumor suppressor in several cancer types, including gynecologic cancers, ovarian clear cell carcinomas, and endometrial cancers.

NCBI Gene ↗ OncoKB ↗
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

Met at very strong: the exon 1 nonsense variant truncates ARID1A at residue 261 of 2,286, removing approximately 88.6% of the protein and predicting NMD.

PM2Supporting
PM2 · supporting

Met at supporting: gnomAD v4.1 AF is 7.01e-07 with zero homozygotes, below the generic PM2 threshold of 0.0001.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) satisfy the generic ACMG/AMP fallback rule for one very strong and one supporting criterion.

02The sources

Evidence at a glance

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

SpliceAI score
0.002 maximum delta

Recorded SpliceAI maximum delta score: 0.002. 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
7 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV61373728, n = 7 times).

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 · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

No ARID1A-specific VCEP framework was retrieved; generic ACMG/AMP definitions were used for PS4, PP4, and BP5.

PS4, PP4, and BP5 lack the required patient-level or case-control evidence and are not assessed.

PP5 and BP6 are not met because the exact variant is absent from ClinVar and has no qualifying expert-panel assertion.

PP3 and BP4 are both upstream not_applicable for this nonsense truncating variant; no in-silico predictor evidence was used.

No ARID1A-specific VCEP or CSPEC was available, so the supplied generic ACMG/AMP population thresholds were used.

Population evidence is rarity-supporting only: PM2 is met at supporting strength; BA1, BS1, and BS2 are not met.

Met · 2

PVS1 Very strongMet at very strong: the exon 1 nonsense variant truncates ARID1A at residue 261 of 2,286, removing approximately 88.6% of the protein and predicting NMD. Details ▾Hide ▴
Reasoning

NM_006015.5:c.782C>A is a nonsense variant producing NP_006006.3:p.(Ser261Ter) in exon 1 of the assessed RefSeq transcript. ARID1A loss of function is established as a disease mechanism in the available gene-level context, making generic PVS1 eligible. The premature stop occurs far upstream of the final exon and is predicted to undergo nonsense-mediated decay under the ClinGen SVI PVS1 framework; the predicted product terminates at residue 261 rather than the 2,286-residue full-length protein, removing approximately 88.6% of the protein. No evidence indicates that the affected exon is biologically irrelevant, alternatively absent from the relevant transcript, or a non-critical distal region, and no specific SVI or VCEP downgrade rule applies. Therefore PVS1 is met at full strength: very strong.

Rule
Generic ClinGen SVI PVS1 framework (PMC6185798): nonsense variant in a biologically relevant coding exon with predicted NMD and no applicable downgrade; retain full PVS1 strength.
Evidence considered
  • VariantValidator reports NM_006015.5:c.782C>A as NP_006006.3:p.(Ser261Ter), a nonsense change in exon 1 of the assessed RefSeq transcript.
  • The gene-level PVS1 context identifies ARID1A loss of function as an established disease mechanism and marks the generic PVS1 gene gate eligible.
  • The ClinGen SVI PVS1 framework states that premature termination codons outside the 3'-most exon or the 3'-most 50 nucleotides of the penultimate exon are generally predicted to trigger NMD, and that full-strength PVS1 is appropriate when no downgrade feature applies.
  • The predicted protein terminates at residue 261 compared with the 2,286-residue reference product, removing approximately 88.6% of the protein; this is not a distal truncation and supports a loss-of-function effect.
Sources
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
PM2 SupportingMet at supporting: gnomAD v4.1 AF is 7.01e-07 with zero homozygotes, below the generic PM2 threshold of 0.0001. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP specification was retrieved, so the supplied generic PM2 supporting threshold of allele frequency <=0.0001 applies. The variant is absent from gnomAD v2.1 and the gnomAD v2.1 non-cancer subset, and gnomAD v4.1 reports only 1/1,427,162 alleles (AF 7.006913020385913e-07), with zero homozygotes; the highest subpopulation AF is 9.118762766267873e-07. These data are below the PM2 threshold and support rarity compatible with a rare disease allele.

Rule
Generic PM2 supporting: AF <=0.0001; no ARID1A-specific VCEP rule was available.
Evidence considered
  • The variant is absent from gnomAD v2.1 and from the gnomAD v2.1 non-cancer subset, whose exome-only figures are the available non-cancer data.
  • gnomAD v4.1 reports 1 alternate allele among 1,427,162 total alleles (AF 7.006913020385913e-07), zero homozygotes, and maximum subpopulation AF 9.118762766267873e-07.
  • The supplied generic PM2 supporting threshold is AF <=0.0001 under the ClinGen SVI recommendation (PMID:25741868).
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 5 · evaluated, threshold not reached

PP5 Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification for NM_006015.5:c.782C>A. Details ▾Hide ▴
Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The ClinVar search found no exact record for NM_006015.5:c.782C>A, with no variation ID, classification, review status, or expert-panel assertion. Therefore the required PP5 trigger is absent; ordinary submissions, aggregate labels, and non-expert assertions were not used.

Rule
PP5 applies only to an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • ClinVar exact-variant search for NM_006015.5:c.782C>A returned no result, no variation ID, and no classification or review status.
  • Because no exact-variant expert-panel Pathogenic/Likely pathogenic assertion exists in the available ClinVar record, PP5 is not triggered.
Sources
clinvar ↗
BA1 Not met: gnomAD v4.1 maximum observed AF is 9.12e-07, far below the generic BA1 threshold of 0.05. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP specification was retrieved, so the generic ACMG/AMP stand-alone BA1 threshold of allele frequency >=0.05 (Richards et al. 2015, PMID:25741868) applies. The variant is present in gnomAD v4.1 at total AF 7.006913020385913e-07 (1/1,427,162 alleles), with the highest reported subpopulation AF 9.118762766267873e-07 in European non-Finnish individuals; both are far below 0.05. gnomAD v2.1 and its non-cancer subset report the variant as absent, and no governing specification requires a different population source.

Rule
Generic ACMG/AMP BA1: AF >=0.05; no ARID1A-specific VCEP rule was available.
Evidence considered
  • gnomAD v4.1 reports 1 alternate allele among 1,427,162 total alleles (AF 7.006913020385913e-07), with the highest observed subpopulation AF 9.118762766267873e-07 in European non-Finnish individuals and zero homozygotes.
  • The generic ACMG/AMP 2015 stand-alone BA1 threshold is allele frequency >=0.05 (Richards et al. 2015, PMID:25741868).
Sources
gnomad_v4 ↗gnomad_v2 ↗
BS1 Not met: the highest gnomAD v4.1 AF is 9.12e-07, far below the supplied generic BS1 threshold of 0.01. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP specification was retrieved, so the supplied generic BS1 threshold of allele frequency >=0.01 applies. The variant's gnomAD v4.1 total AF is 7.006913020385913e-07 and its highest reported subpopulation AF is 9.118762766267873e-07 in European non-Finnish individuals, both well below 0.01. gnomAD v2.1 and the gnomAD v2.1 non-cancer subset report absence; the observed frequency does not support a benign frequency inconsistent with the disease model.

Rule
Generic BS1: AF >=0.01; no ARID1A-specific VCEP rule was available.
Evidence considered
  • gnomAD v4.1 reports total AF 7.006913020385913e-07 and maximum observed subpopulation AF 9.118762766267873e-07 in European non-Finnish individuals, with zero homozygotes.
  • The supplied generic BS1 threshold is AF >=0.01; generic per-gene derivation is preferred (Whiffin et al. 2017, PMID:28518168).
Sources
gnomad_v4 ↗gnomad_v2 ↗
BS2 Not met: gnomAD v4.1 shows one alternate allele but zero homozygotes, providing no BS2-inconsistent healthy-genotype observation. Details ▾Hide ▴
Reasoning

BS2 requires observation of the variant in healthy adults in a context inconsistent with the expected disease model, such as homozygotes for a fully penetrant dominant disorder or affected-state genotypes for a recessive disorder. gnomAD v4.1 reports one heterozygous alternate allele and zero homozygotes; the highest subpopulation also has zero homozygotes. Therefore, the available population data do not meet BS2.

Rule
Generic BS2: healthy-adult observation inconsistent with the disease model, including homozygotes where applicable; no qualifying observation was found.
Evidence considered
  • gnomAD v4.1 reports total AC 1, total AN 1,427,162, and total homozygote count 0; the European non-Finnish maximum-frequency subpopulation likewise has AC 1 and homozygote count 0.
  • The variant is absent from gnomAD v2.1 and its non-cancer subset, so there is no additional healthy-population homozygote observation.
Sources
gnomad_v4 ↗gnomad_v2 ↗
BP6 Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for NM_006015.5:c.782C>A. Details ▾Hide ▴
Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The ClinVar search found no exact record for NM_006015.5:c.782C>A, with no variation ID, classification, review status, or expert-panel assertion. Therefore the required BP6 trigger is absent; ordinary submissions, aggregate labels, and non-expert assertions were not used.

Rule
BP6 applies only to an exact-variant ClinVar expert-panel Benign or Likely benign classification; ordinary submissions, aggregate labels, and non-expert assertions do not qualify.
Evidence considered
  • ClinVar exact-variant search for NM_006015.5:c.782C>A returned no result, no variation ID, and no classification or review status.
  • Because no exact-variant expert-panel Benign/Likely benign assertion exists in the available ClinVar record, BP6 is not triggered.
Sources
clinvar ↗

Not assessed · 11 · no assessment recorded

PS2 Not assessed: no parental genotypes or confirmed maternity and paternity are documented to establish a de novo occurrence. Details ▾Hide ▴
Reasoning

No proband-level parental testing or other documented evidence establishes that NM_006015.5:c.782C>A (NP_006006.3:p.(Ser261Ter)) arose de novo. The available case materials do not provide parental genotypes, maternity/paternity confirmation, or parental phenotype information; therefore PS2 cannot be assessed.

Rule
Generic ACMG/AMP PS2: de novo occurrence in a patient with confirmed maternity and paternity; stronger evidence requires confirmed de novo status and appropriate phenotype consistency.
Evidence considered
  • The case materials identify the variant as NM_006015.5:c.782C>A, predicted to encode NP_006006.3:p.(Ser261Ter), but provide no parental testing results.
  • No proband-level de novo observation, parental genotype, or maternity/paternity confirmation is available for PS2 assessment.
Still missing
  • Parental genotype results for the proband's mother and father are not documented.
  • Confirmed maternity and paternity are not documented.
  • Parental phenotype information is not documented.
PS3 Not assessed: no validated functional assay of ARID1A c.782C>A or p.Ser261Ter was identified to establish a PS3 strength. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP specification was identified, so the generic ACMG/AMP framework applies. The variant is NM_006015.5:c.782C>A, predicted to introduce NP_006006.3:p.(Ser261Ter), but the available literature reports general ARID1A loss-of-function biology rather than a validated functional assay of this exact variant. The reviewed studies do not provide variant-specific assay results, appropriate controls, or a calibrated functional readout that could establish PS3 at any strength. Therefore PS3 is not assessed.

Rule
generic ACMG/AMP PS3: requires well-established functional studies relevant to the variant and disease mechanism
Evidence considered
  • The reviewed ARID1A studies describe general loss-of-function biology, tumor-suppressor activity, or experimental ARID1A deletion/restoration models, but none reports a functional assay of NM_006015.5:c.782C>A or NP_006006.3:p.(Ser261Ter).
  • PMID:21900401 evaluated restoration or knockdown of ARID1A in cancer and epithelial cell models with proliferation, cell-cycle, xenograft, and molecular readouts; the extracted finding states that the case variant was not mentioned.
  • PMID:22009941 used Sanger sequencing across 759 neoplasms and characterized somatic ARID1A mutations, but did not test the case variant experimentally.
  • PMID:24899687 and PMID:25625625 used conditional mouse models of Arid1a loss with cooperating alterations; these are gene-level biological studies and not variant-specific assays.
Still missing
  • A validated assay directly testing ARID1A c.782C>A or p.Ser261Ter, with appropriate positive and negative controls and a disease-relevant readout, is needed for PS3 assessment.
Sources
PMID:21900401 ↗PMID:22009941 ↗PMID:24899687 ↗PMID:25625625 ↗
PS4 Not assessed: no case-control counts, odds ratio, confidence interval, or p-value demonstrate enrichment of NM_006015.5:c.782C>A in affected individuals. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP framework was retrieved, so the generic ACMG/AMP definition applies: PS4 requires a statistically significant excess of the variant in affected individuals compared with controls. The available evidence contains no case-control counts, odds ratio, confidence interval, p-value, or affected-case cohort for NM_006015.5:c.782C>A. The general somatic ARID1A literature is not exact-variant case-control evidence and cannot establish PS4.

Rule
Generic ACMG/AMP PS4: prevalence of the variant is significantly increased in affected individuals compared with controls; no applicable ARID1A-specific VCEP rule was retrieved.
Evidence considered
  • No affected-versus-control prevalence data, odds ratio, confidence interval, or p-value were provided for NM_006015.5:c.782C>A.
  • The available literature extracts concern general ARID1A somatic mutation prevalence or functional tumor models and do not mention this exact variant; they therefore do not establish PS4.
Still missing
  • A case-control dataset specific to NM_006015.5:c.782C>A is unavailable.
  • No statistically testable enrichment measure or governing threshold is available.
PM3 Not assessed: no affected-proband genotype, second pathogenic allele, phase result, or established recessive inheritance context is available for PM3. Details ▾Hide ▴
Reasoning

No governing ARID1A VCEP or gene-specific framework is available, so generic ACMG/AMP is used. PM3 requires an affected individual with the variant in trans with a pathogenic or likely pathogenic variant for a recessive disorder. The available case evidence contains no affected-proband genotype, second pathogenic allele, phase determination, family segregation, or established recessive inheritance context for ARID1A. Therefore PM3 cannot be assessed rather than applied.

Rule
Generic PM3: pathogenic or likely pathogenic variant observed in trans with the variant being evaluated in an affected individual with a recessive disorder; phase must be established or sufficiently supported.
Evidence considered
  • The case identifies NM_006015.5:c.782C>A (NP_006006.3:p.(Ser261Ter)) but reports no second allele, phase information, affected-proband observation, or family segregation data.
  • No ARID1A-specific VCEP or CSPEC specification is available; the case framework therefore falls back to generic ACMG/AMP criteria.
  • The available literature extracts concern general ARID1A loss-of-function or somatic cancer biology and do not report this variant in an affected individual with a phased second allele, so they do not establish PM3 evidence.
Still missing
  • Affected-proband genotype and phenotype context
  • A second pathogenic or likely pathogenic variant, if present
  • Experimental or pedigree-based phase determination
  • Disease inheritance mode relevant to PM3
PM6 Not assessed: no clinical case report or phenotype-supported presumed de novo occurrence is documented without parental testing. Details ▾Hide ▴
Reasoning

No proband-level report documents a presumed de novo occurrence of NM_006015.5:c.782C>A without parental testing. The available materials contain no clinical case description, parental genotype information, or phenotype-supported presumption sufficient for PM6; therefore PM6 cannot be assessed.

Rule
Generic ACMG/AMP PM6: assumed de novo occurrence in a patient with a phenotype consistent with the gene-related disorder when maternity and paternity are unconfirmed or parental testing is unavailable.
Evidence considered
  • The available case materials do not document a proband phenotype, a clinical case observation, or a presumed de novo origin for this variant.
  • No parental testing-independent evidence supports PM6.
Still missing
  • A proband-level clinical observation is not documented.
  • The proband's phenotype and its consistency with ARID1A-related disease are not documented.
  • Any presumption of de novo origin without parental testing is not documented.
PP1 Not assessed: no affected relatives, informative meioses, or variant-positive family segregation data are documented. Details ▾Hide ▴
Reasoning

No affected relatives carrying NM_006015.5:c.782C>A and no informative meioses are documented. The available materials provide no family pedigree, segregation analysis, affected-relative genotypes, or phenotype assessments; therefore PP1 cannot be assessed.

Rule
Generic ACMG/AMP PP1: co-segregation with disease in multiple affected family members; strength depends on the number and informativeness of meioses and phenotype consistency.
Evidence considered
  • No segregation study or family-level genotype data for NM_006015.5:c.782C>A are available.
  • No affected-relative count, informative meioses, or phenotype concordance data are available to support PP1 strength.
Still missing
  • Family pedigree and informative meiosis count are not documented.
  • Genotypes of affected relatives are not documented.
  • Phenotype consistency among affected relatives is not documented.
PP4 Not assessed: no patient phenotype, family history, or phenotype-specific likelihood information is available to establish a highly specific ARID1A-associated presentation. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP framework was retrieved, so the generic ACMG/AMP definition applies: PP4 requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The case materials provide no individual clinical phenotype, disease diagnosis, family history, or phenotype-specific likelihood information for this variant. ARID1A tumor-gene context and a predicted truncating consequence do not establish phenotype specificity.

Rule
Generic ACMG/AMP PP4: patient's phenotype or family history is highly specific for a disease with a single genetic etiology; no applicable ARID1A-specific VCEP rule was retrieved.
Evidence considered
  • No patient phenotype, family history, or disease-specific clinical presentation was supplied for NM_006015.5:c.782C>A.
  • General ARID1A cancer biology and the predicted p.(Ser261Ter) consequence are not phenotype-specific evidence for PP4.
Still missing
  • Patient-level phenotype and confirmed clinical diagnosis are unavailable.
  • No phenotype specificity or likelihood estimate is available.
BS3 Not assessed: no validated normal-function assay of ARID1A c.782C>A or p.Ser261Ter was identified to establish BS3. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP specification was identified, so the generic ACMG/AMP framework applies. The available evidence includes no validated functional study demonstrating that NM_006015.5:c.782C>A or NP_006006.3:p.(Ser261Ter) has normal function. The reviewed papers concern general ARID1A loss-of-function biology, cancer models, or population-level mutation characterization and do not supply a benign functional result, assay controls, or a disease-relevant normal-function threshold for this exact variant. Therefore BS3 is not assessed.

Rule
generic ACMG/AMP BS3: requires well-established functional studies showing no damaging effect on protein function or splicing
Evidence considered
  • None of the reviewed sources reports normal functional activity for NM_006015.5:c.782C>A or NP_006006.3:p.(Ser261Ter).
  • PMID:21900401 reports effects of wild-type ARID1A restoration and ARID1A knockdown, not a normal-function result for the case variant.
  • PMID:22009941 identifies truncating ARID1A mutations in tumors but does not perform a benign functional assay of the case variant.
  • PMID:24899687 and PMID:25625625 assess consequences of Arid1a deletion in mouse tumor models and therefore do not establish normal function for this variant.
Still missing
  • A validated disease-relevant assay directly testing ARID1A c.782C>A or p.Ser261Ter and demonstrating normal function with appropriate controls is needed for BS3 assessment.
Sources
PMID:21900401 ↗PMID:22009941 ↗PMID:24899687 ↗PMID:25625625 ↗
BS4 Not assessed: no appropriately evaluated unaffected relatives with documented negative genotypes are available for non-segregation evidence. Details ▾Hide ▴
Reasoning

No unaffected relatives who are expected to be at risk and have been adequately evaluated are documented as lacking NM_006015.5:c.782C>A. The available materials provide no pedigree, unaffected-relative genotypes, ages, or phenotype information; therefore BS4 cannot be assessed.

Rule
Generic ACMG/AMP BS4: lack of segregation in affected family members or presence of the variant in unaffected family members when the phenotype and age make non-segregation informative.
Evidence considered
  • No unaffected-relative testing or family pedigree is documented for this variant.
  • The available materials do not establish that any negative relatives were old enough, clinically evaluated, and appropriately at risk for BS4.
Still missing
  • At-risk unaffected relatives are not identified.
  • Genotype results for unaffected relatives are not documented.
  • Relative ages, clinical evaluation, and expected disease penetrance are not documented.
BP2 Not assessed: no second variant or phase result shows this allele in cis or trans with a pathogenic variant, and gnomAD provides no phase information. Details ▾Hide ▴
Reasoning

No governing ARID1A VCEP or gene-specific framework is available, so generic ACMG/AMP is used. BP2 requires the variant to be observed in trans with a pathogenic variant in a disorder where the gene is not fully penetrant, or in cis with a pathogenic variant. The available case evidence contains no second variant, phase result, proband genotype, or family data demonstrating either configuration. The variant's presence in gnomAD v4.1 at AF 7.006913020385913e-07 (1/1,427,162 alleles; zero homozygotes) does not provide cis/trans evidence. Therefore BP2 cannot be assessed.

Rule
Generic BP2: variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or observed in cis with a pathogenic variant; phase and the applicable inheritance/penetrance context must be established.
Evidence considered
  • The case provides no cis/trans phase data, second variant, affected-proband genotype, or family segregation information.
  • gnomAD v4.1 reports AF 7.006913020385913e-07 with 1 alternate allele among 1,427,162 alleles and zero homozygotes; this population observation cannot establish cis or trans phase with another pathogenic variant.
  • No ARID1A-specific VCEP or CSPEC specification is available; the case framework therefore falls back to generic ACMG/AMP criteria.
Still missing
  • A second variant identified in the same proband or family
  • Experimental or pedigree-based cis/trans phase determination
  • Relevant inheritance and penetrance context
Sources
gnomad_v4 ↗
BP5 Not assessed: no qualifying patient case documents an alternate molecular basis for the disease instead of NM_006015.5:c.782C>A. Details ▾Hide ▴
Reasoning

No applicable ARID1A-specific VCEP framework was retrieved, so the generic ACMG/AMP definition applies: BP5 requires the variant to be found in a case with an alternate molecular basis for the disease. The available materials contain no qualifying patient-level case with an established alternative molecular diagnosis, and general somatic ARID1A cancer observations do not establish BP5.

Rule
Generic ACMG/AMP BP5: variant found in a case with an alternate molecular basis for the disease; no applicable ARID1A-specific VCEP rule was retrieved.
Evidence considered
  • No qualifying affected case with an established alternate molecular basis was provided.
  • The available exact-variant evidence is limited to somatic database reporting and does not demonstrate BP5.
Still missing
  • No patient-level case with a confirmed alternate molecular explanation is available.
  • No disease-specific molecular differential or exclusion evidence is available.
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1 N/APM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM4 N/APM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM5 N/APM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP2 N/APP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP3 N/ANot applicable: c.782C>A produces p.(Ser261Ter), a nonsense truncating variant outside PP3 scope. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_006015.5:c.782C>A produces NP_006006.3:p.(Ser261Ter), a nonsense truncating variant. PP3 is restricted here to missense variants or splice-region/intronic variants evaluated through the SpliceAI path; therefore SpliceAI and missense predictor scores are not evaluated.

Evidence considered
  • Variant normalization identifies NM_006015.5:c.782C>A as NP_006006.3:p.(Ser261Ter), a nonsense truncating change.
  • The governing framework is generic ACMG fallback because no applicable ARID1A VCEP or ClinGen specification was found; scope is resolved before predictor evaluation.
BP1 N/ABP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_missense
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3 N/ABP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP4 N/ANot applicable: c.782C>A produces p.(Ser261Ter), a nonsense truncating variant outside BP4 scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_006015.5:c.782C>A produces NP_006006.3:p.(Ser261Ter), a nonsense truncating variant. BP4 is restricted here to missense variants or splice-region/intronic variants evaluated through the SpliceAI path; therefore SpliceAI and missense predictor scores are not evaluated.

Evidence considered
  • Variant normalization identifies NM_006015.5:c.782C>A as NP_006006.3:p.(Ser261Ter), a nonsense truncating change.
  • The governing framework is generic ACMG fallback because no applicable ARID1A VCEP or ClinGen specification was found; scope is resolved before predictor evaluation.
BP7 N/ABP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Identifiers

Gene
ARID1A
Transcript
NM_006015.5
Coding (HGVS c.)
NM_006015.5:c.782C>A
Protein (HGVS p.)
NP_006006.3:p.(Ser261Ter)
GRCh38
chr1:26697185 C>A
GRCh37
chr1:27023676 C>A
Location and type
Exon 1 · nonsense
COSMIC
COSV61373728

Gene diagram

Every interpreted variant in ARID1A, mapped onto the exon structure of NM_006015.5. Select a row to find it on the plot.

ARID1ANM_006015.5
Fetching transcript structure from UCSC…
gnomAD v4.1 1 / 1,427,162 alleles AF 7.01e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 7e-07 · 1 / 1,427,162 alleles · 0 hom
European (non-Finnish)1 / 1,096,640 9.1e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 7.00691e-07; MAF= 0.00007%, 1/1427162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.11876e-07; MAF= 0.00009%, 1/1096640 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -14 bp
0.000
SpliceAI acceptor gainat -342 bp
0.000
SpliceAI donor lossat +355 bp
0.000
SpliceAI donor gainat -76 bp
0.002
Pangolin splice lossmagnitude shown
-0.002
Pangolin splice gain
0.005

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 N/ANot applicable: c.782C>A produces p.(Ser261Ter), a nonsense truncating variant outside PP3 scope. Details ▾Hide ▴
Reasoning

PP3 is not applicable because NM_006015.5:c.782C>A produces NP_006006.3:p.(Ser261Ter), a nonsense truncating variant. PP3 is restricted here to missense variants or splice-region/intronic variants evaluated through the SpliceAI path; therefore SpliceAI and missense predictor scores are not evaluated.

Evidence considered
  • Variant normalization identifies NM_006015.5:c.782C>A as NP_006006.3:p.(Ser261Ter), a nonsense truncating change.
  • The governing framework is generic ACMG fallback because no applicable ARID1A VCEP or ClinGen specification was found; scope is resolved before predictor evaluation.
BP4 N/ANot applicable: c.782C>A produces p.(Ser261Ter), a nonsense truncating variant outside BP4 scope. Details ▾Hide ▴
Reasoning

BP4 is not applicable because NM_006015.5:c.782C>A produces NP_006006.3:p.(Ser261Ter), a nonsense truncating variant. BP4 is restricted here to missense variants or splice-region/intronic variants evaluated through the SpliceAI path; therefore SpliceAI and missense predictor scores are not evaluated.

Evidence considered
  • Variant normalization identifies NM_006015.5:c.782C>A as NP_006006.3:p.(Ser261Ter), a nonsense truncating change.
  • The governing framework is generic ACMG fallback because no applicable ARID1A VCEP or ClinGen specification was found; scope is resolved before predictor evaluation.
BP7 N/ABP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_006015.5:c.782C>A in ARID1A is a nonsense substitution introducing a premature stop codon predicted to produce NP_006006.3:p.(Ser261Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: nonsense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.66.

4 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

  • ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers.
    The paper does not mention ARID1A c.782C>A or NP_006006.3:p.(S261*). It investigates ARID1A loss of function more generally: restoring wild-type ARID1A reduced proliferation, S-phase cells, and xenograft tumor weight in carcinoma models, while knockdown increased proliferation and tumorigenicity.
    Does not name this variant
    PMID 21900401 ↗
    Quoted passage
    Because the majority of somatic mutations involving ARID1A in human cancers are insertions/deletions causing frameshift or nonsense mutations, ARID1A was thought to behave as a tumor suppressor gene, but direct evidence of its tumor suppressor activity has not been demonstrated.

    Introduction; Results, ‘Restoring ARID1A expression suppresses tumor growth’ and ‘Silencing of ARID1A expression enhances cellular proliferation and tumorigenicity’

  • Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types.
    The paper does not explicitly mention ARID1A c.782C>A or NP_006006.3:p.(S261*). It reports somatic ARID1A mutations in 43 of 759 neoplasms, including nonsense, out-of-frame, and in-frame indels, and interprets truncating mutations as inactivating; it does not experimentally assay the case variant.
    Does not name this variant
    PMID 22009941 ↗
    Quoted passage
    Somatic mutations were identified in 43 of the 759 neoplasms studied (6%) (Table 1).

    Results, paragraph beginning ‘Somatic mutations were identified’; Figure 1 legend

  • Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis.
    The paper does not mention ARID1A c.782C>A or NP_006006.3:p.(S261*). In a conditional mouse ovarian surface epithelium model, Arid1a deletion alone did not produce ovarian lesions, whereas combined Arid1a and Pten deletion produced ovarian tumors or hyperplasia, showing general gene-level tumor-suppressor biology rather than a case-variant assay.
    Does not name this variant
    PMID 24899687 ↗
    Quoted passage
    The great majority of ARID1A mutations are frameshift or nonsense mutations that occur throughout the coding region, suggesting that ARID1A functions as a tumor suppressor.

    Introduction; Results; Summary

  • Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling.
    The paper does not mention ARID1A c.782C>A or NP_006006.3:p.(S261*). In conditional mouse models, Arid1a loss alone did not produce ovarian tumors, while combined Arid1a loss and activating PIK3CA H1047R produced ovarian tumors; this is general model biology, not a functional test of the case variant.
    Does not name this variant
    PMID 25625625 ↗
    Quoted passage
    The observation that ARID1A loss does not lead to tumor formation supports the notion that ARID1A mutations require additional mutational ‘hits’ in the OSE before tumorigenesis can ensue26.

    Results, ‘Generation of a novel Arid1a conditional allele’

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

gnomAD v4.1 1 / 1,427,162 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.002 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

This variant is present in gnomAD v4.1 (AF= 7.00691e-07; MAF= 0.00007%, 1/1427162 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 9.11876e-07; MAF= 0.00009%, 1/1096640 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Not available in 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 = 0.00). BayesDel score = 0.66.

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 previously been reported in somatic cancers (COSMIC; COSV61373728, n = 7 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.