Variant classification summary

NM_006015.5:c.2297A>T

ARID1A · NP_006006.3:p.(Gln766Leu) · NM_006015.5

GRCh37: chr1:27088688 A>T · GRCh38: chr1:26762197 A>T

Gene: ARID1A Transcript: NM_006015.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

ARID1A

Transcript

NM_006015.5

Protein

NP_006006.3:p.(Gln766Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.

2

BP4 (Supporting): REVEL score 0.256 meets the <=0.290 supporting threshold for benign prediction.

3

Final: VUS - one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) constitute conflicting evidence that meets no ACMG/AMP 2015 Benign, Likely Benign, Likely Pathogenic, or Pathogenic combination.

Final determination: Generic ACMG/AMP 2015 fallback: 1 supporting pathogenic criterion (PM2) plus 1 supporting benign criterion (BP4) does not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule, so the variant is classified as Variant of Uncertain Significance.

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	Not applicable: this missense change does not create a premature stop, frameshift, or splice-site loss that would trigger nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to compare this amino acid change against an established pathogenic variant at the same residue.
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo occurrence data were available for this variant.
PS3	Not assessed	Not assessed: no published functional assay data (e.g., transcriptional or chromatin-remodeling activity) were available for this variant.
PS4	Not assessed	Not assessed: no affected-case series or case-control data were available to establish increased prevalence in affected individuals.
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether this variant lies in a well-established functional domain.
PM2	Met	Met (supporting): this variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence of a second ARID1A variant in trans or a recessive disease pattern was available.	final_classification_framework
PM4	N/A	Not applicable: this missense change does not alter protein length, so the in-frame insertion/deletion or stop-loss criterion cannot apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to determine whether a different pathogenic missense change exists at this same residue.
PM6	Not assessed	Not assessed: no parental testing or phenotype data were available to support an unconfirmed de novo event.
PP1	Not assessed	Not assessed: no family segregation data (affected or unaffected relatives tested for this variant) were available.
PP2	Not assessed	Not assessed: insufficient evidence was available to determine the proportion of benign missense variation in this gene.
PP3	Not met	Not met: REVEL score 0.256 falls below the >=0.644 supporting threshold for pathogenic prediction.	revel spliceai
PP4	Not assessed	Not assessed: no patient phenotype description was available to establish a highly specific disease pattern.
PP5	Not met	Not met: this exact variant is absent from ClinVar, so no expert-panel pathogenic classification exists.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, so no allele frequency approaching the >5% BA1 threshold was observed.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: the variant is absent from gnomAD, so no allele frequency above the disease-specific expected maximum was demonstrated.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no healthy adult homozygote or documented unaffected individual carrying this variant was identified.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no published functional assay data demonstrating a benign effect were available for this variant.
BS4	Not assessed	Not assessed: no family data showing affected relatives who do not carry the variant were available.
BP1	Not assessed	Not assessed: insufficient evidence was available to determine whether a stop codon is created within the last exon.
BP2	Not assessed	Not assessed: no family or phase data were available to determine whether this variant occurs with a pathogenic variant in cis or a benign variant in trans.	final_classification_framework
BP3	N/A	Not applicable: this missense change does not insert or delete protein sequence within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL score 0.256 meets the <=0.290 supporting threshold for benign prediction.	revel spliceai
BP5	Not assessed	Not assessed: no alternative molecular diagnosis explaining the patient's phenotype was documented.
BP6	Not met	Not met: this exact variant is absent from ClinVar, so no expert-panel benign classification exists.	clinvar
BP7	N/A	Not applicable: this criterion requires a synonymous variant, but this change is a missense that alters the protein sequence.	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.