Variant classification summary

NM_006015.5:c.782C>A

ARID1A · NP_006006.3:p.(Ser261Ter) · NM_006015.5

GRCh37: chr1:27023676 C>A · GRCh38: chr1:26697185 C>A

Gene: ARID1A Transcript: NM_006015.5

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

ARID1A

Transcript

NM_006015.5

Protein

NP_006006.3:p.(Ser261Ter)

gnomAD AF

7.006913020385913e-07 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: the exon 1 nonsense variant predicts NMD and removes approximately 88.6% of ARID1A.

2

PM2 supporting: gnomAD v4.1 reports an allele frequency of 7.01e-07 with zero homozygotes.

Final determination: Under the generic ACMG/AMP fallback, one very strong pathogenic criterion plus one supporting pathogenic criterion leads to a Likely Pathogenic classification.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 (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.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental genotypes or confirmed maternity and paternity are documented to establish a de novo occurrence.
PS3	Not assessed	Not assessed: no validated functional assay of ARID1A c.782C>A or p.Ser261Ter was identified to establish a PS3 strength.	PMID:21900401 PMID:22009941 PMID:24899687 PMID:25625625
PS4	Not assessed	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.
PM1	N/A	PM1 (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.	generic_acmg_combination_rules
PM2	Met	Met at supporting: gnomAD v4.1 AF is 7.01e-07 with zero homozygotes, below the generic PM2 threshold of 0.0001.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband genotype, second pathogenic allele, phase result, or established recessive inheritance context is available for PM3.
PM4	N/A	PM4 (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.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (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.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no clinical case report or phenotype-supported presumed de novo occurrence is documented without parental testing.
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or variant-positive family segregation data are documented.
PP2	N/A	PP2 (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.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.782C>A produces p.(Ser261Ter), a nonsense truncating variant outside PP3 scope.
PP4	Not assessed	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	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic classification for NM_006015.5:c.782C>A.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum observed AF is 9.12e-07, far below the generic BA1 threshold of 0.05.	gnomad_v4 gnomad_v2
BS1	Not met	Not met: the highest gnomAD v4.1 AF is 9.12e-07, far below the supplied generic BS1 threshold of 0.01.	gnomad_v4 gnomad_v2
BS2	Not met	Not met: gnomAD v4.1 shows one alternate allele but zero homozygotes, providing no BS2-inconsistent healthy-genotype observation.	gnomad_v4 gnomad_v2
BS3	Not assessed	Not assessed: no validated normal-function assay of ARID1A c.782C>A or p.Ser261Ter was identified to establish BS3.	PMID:21900401 PMID:22009941 PMID:24899687 PMID:25625625
BS4	Not assessed	Not assessed: no appropriately evaluated unaffected relatives with documented negative genotypes are available for non-segregation evidence.
BP1	N/A	BP1 (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.	generic_acmg_combination_rules
BP2	Not assessed	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.	gnomad_v4
BP3	N/A	BP3 (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.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.782C>A produces p.(Ser261Ter), a nonsense truncating variant outside BP4 scope.
BP5	Not assessed	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	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification for NM_006015.5:c.782C>A.	clinvar
BP7	N/A	BP7 (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.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.