Variant classification summary

NM_006015.5:c.673C>T

ARID1A · NP_006006.3:p.(Pro225Ser) · NM_006015.5

GRCh37: chr1:27023567 C>T · GRCh38: chr1:26697076 C>T

Gene: ARID1A Transcript: NM_006015.5

Final call

VUS

PM2 supporting

Variant details

Gene

ARID1A

Transcript

NM_006015.5

Protein

NP_006006.3:p.(Pro225Ser)

gnomAD AF

2.672506985265133e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 shows extreme rarity at 4/1,496,722 alleles (AF 2.67251e-06) with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not satisfy any definitive pathogenic, likely pathogenic, likely benign, or benign combination, resulting in VUS.

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	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_006015.5:c.673C>T in ARID1A is a missense substitution predicted to produce NP_006006.3:p.(Pro225Ser). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1'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
PS1	Not assessed	Not assessed: no validated pathogenic comparator producing the same p.Pro225Ser amino-acid change was identified.	clinvar
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, maternity/paternity confirmation, or independent confirmed de novo observations are documented.
PS3	Not assessed	Not assessed: no variant-specific validated functional assay, assay controls, or quantitative result was available to support a damaging functional conclusion.	oncokb
PS4	Not assessed	Not assessed: no exact-variant case-control counts or enrichment statistic are available to establish increased prevalence of ARID1A c.673C>T.
PM1	Not assessed	Not assessed: hotspot evidence is negative, while no authoritative ARID1A domain boundaries establish whether residue 225 is functionally critical.
PM2	Met	Met at supporting strength: gnomAD v4.1 shows 4/1,496,722 alleles (AF 2.67251e-06), zero homozygotes, and grpmax FAF 3.804e-05.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected proband, second pathogenic variant, phase information, or inheritance mode is documented for the tested ARID1A variant.	generic_acmg_combination_rules
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.673C>T in ARID1A is a missense substitution predicted to produce NP_006006.3:p.(Pro225Ser). 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	Not assessed	Not assessed: no validated pathogenic alternate missense variant at ARID1A residue 225 was available for PM5 comparison.	pm5_candidates
PM6	Not assessed	Not assessed: no affected-proband de novo observation or parental testing is documented, so presumed de novo evidence cannot be evaluated.
PP1	Not assessed	Not assessed: no relatives, informative meioses, pedigree, or variant–phenotype segregation data are reported.
PP2	Not met	Not met: ARID1A missense mechanism is unestablished, and gnomAD v4.1 shows AF 2.67251e-06 without proving PP2's gene-level requirement.	gnomad_v4 clinvar
PP3	Not assessed	Not assessed: the missense variant lacks an available calibrated REVEL or BayesDel score, while SpliceAI is not the applicable path for this exonic missense change.
PP4	Not assessed	Not assessed: no proband phenotype or disease-specific clinical presentation is available to evaluate phenotype specificity for ARID1A c.673C>T.
PP5	Not met	Not met: ClinVar has no record for this exact variant, so no expert-panel Pathogenic or Likely pathogenic classification exists to support PP5.	clinvar
BA1	Not met	Not met: gnomAD v4.1 maximum reported population AF is 1.11788e-04, far below the generic BA1 threshold of 5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 3.804e-05, with no frequency evidence showing the variant is too common for a rare ARID1A disorder.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: gnomAD v4.1 reports zero homozygotes and only 4 total alleles, providing no required healthy-adult observation pattern for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated functional assay, assay controls, or quantitative result was available to support a benign functional conclusion.	oncokb
BS4	Not assessed	Not assessed: no unaffected relatives with reliable phenotypes and genotypes are available to evaluate non-segregation.
BP1	Not assessed	Not assessed: ARID1A loss-of-function evidence does not quantify whether disease is predominantly truncating, and gnomAD AF is 2.67251e-06.	gnomad_v4
BP2	Not assessed	Not assessed: no paired pathogenic allele, family or proband observation, phase result, or inheritance mode is documented to evaluate BP2.	generic_acmg_combination_rules
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.673C>T in ARID1A is a missense substitution predicted to produce NP_006006.3:p.(Pro225Ser). 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	Not assessed	Not assessed: the missense variant lacks an available calibrated REVEL or BayesDel score, while SpliceAI is not the applicable path for this exonic missense change.
BP5	Not assessed	Not assessed: no alternate molecular diagnosis or other proband-level evidence is available to determine whether another cause explains the phenotype.
BP6	Not met	Not met: ClinVar has no record for this exact variant, so no expert-panel Benign or Likely benign classification exists to support BP6.	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.673C>T in ARID1A is a missense substitution predicted to produce NP_006006.3:p.(Pro225Ser). 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

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