Classification rationale

PVS1PM2 Likely Pathogenic

ARID1A c.782C>A nonsense · exon 1

PVS1 very strong: the exon 1 nonsense variant predicts NMD and removes approximately 88.6% of ARID1A. PM2 supporting: gnomAD v4.1 reports an allele frequency of 7.01e-07 with zero homozygotes.

PVS1 + PM2 → Likely Pathogenic

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.

Gene diagram · NM_006015.5 · variants mapped to exon structure

ARID1A NM_006015.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

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.

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.

pvs1_generic_framework ↗

PM2 supporting Pathogenic

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

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).

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 5 not met · 11 not assessed

Pathogenic

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

PS3 Not assessed: no validated functional assay of ARID1A c.782C>A or p.Ser261Ter was identified to establish a PS3 strength.

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.

PM3 Not assessed: no affected-proband genotype, second pathogenic allele, phase result, or established recessive inheritance context is available for PM3.

PM6 Not assessed: no clinical case report or phenotype-supported presumed de novo occurrence is documented without parental testing.

PP1 Not assessed: no affected relatives, informative meioses, or variant-positive family segregation data are documented.

PP4 Not assessed: no patient phenotype, family history, or phenotype-specific likelihood information is available to establish a highly specific ARID1A-associated presentation.

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

Benign

BA1 Not met: gnomAD v4.1 maximum observed AF is 9.12e-07, far below the generic BA1 threshold of 0.05.

BS1 Not met: the highest gnomAD v4.1 AF is 9.12e-07, far below the supplied generic BS1 threshold of 0.01.

BS2 Not met: gnomAD v4.1 shows one alternate allele but zero homozygotes, providing no BS2-inconsistent healthy-genotype observation.

BS3 Not assessed: no validated normal-function assay of ARID1A c.782C>A or p.Ser261Ter was identified to establish BS3.

BS4 Not assessed: no appropriately evaluated unaffected relatives with documented negative genotypes are available for non-segregation evidence.

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.

BP5 Not assessed: no qualifying patient case documents an alternate molecular basis for the disease instead of NM_006015.5:c.782C>A.

BP6 Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for NM_006015.5:c.782C>A.

N/A · 10 PS1 · PM1 · PM4 · PM5 · PP2 · PP3 · BP1 · BP3 · BP4 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

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).

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

7e-05% · 1 / 1,427,162
0 hom

European (non-Finnish)

1 / 1,096,640

9.1e-05%

+ 9 not observed (Remaining individuals, 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 is absent from ClinVar.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61373728, n = 7 times).

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 · 4 PMIDs not cited in assessment

21900401 ↗ ARID1A, a factor that promotes formation of SWI/SNF-mediated chromatin remodeling, is a tumor suppressor in gynecologic cancers. ONCOKB

22009941 ↗ Somatic mutations in the chromatin remodeling gene ARID1A occur in several tumor types. ONCOKB

24899687 ↗ Roles of deletion of Arid1a, a tumor suppressor, in mouse ovarian tumorigenesis. ONCOKB

25625625 ↗ Coexistent ARID1A-PIK3CA mutations promote ovarian clear-cell tumorigenesis through pro-tumorigenic inflammatory cytokine signalling. ONCOKB

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