NM_002944.2:c.6068A>T

ROS1 · NP_002935.2:p.(Tyr2023Phe) · NM_002944.2

GRCh37: chr6:117638373 T>A · GRCh38: chr6:117317210 T>A

Gene: ROS1 Transcript: NM_002944.2

Final call

VUS

PM2 supporting

Variant details

Gene

ROS1

Transcript

NM_002944.2

Protein

NP_002935.2:p.(Tyr2023Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Supporting): absent (AF = 0) from gnomAD v2.1 exomes, gnomAD v4.1 exomes, and gnomAD-Canada v1.0 genomes, three independent population datasets.

VUS: a single Supporting PM2 satisfies no ACMG/AMP 2015 combination rule for Pathogenic, Likely Pathogenic, Benign, or Likely Benign.

Final determination: Under the generic ACMG/AMP 2015 fallback combination rules (no ROS1 VCEP/CSPEC exists; final_classification_framework found=false), only PM2 at Supporting strength is met; no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination is satisfied, so the variant resolves to Uncertain Significance (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	Not applicable: PVS1 applies only to null variants, and this missense substitution (p.Tyr2023Phe) triggers no null-variant mechanism.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no ClinVar record or literature reports exist, so no same-amino-acid pathogenic comparator (p.Tyr2023Phe) was available.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband phenotype, family history, or parental genotyping data were available to evaluate a de novo origin.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional studies exist for this variant; OncoKB reports unknown oncogenic effect.	oncokb spliceai generic_acmg_combination_rules
PS4	Not assessed	Not assessed: no case-control or cohort allele-frequency comparison exists for this variant.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM1	Not met	Not met: no statistically significant hotspot at ROS1 Y2023, and no curated ROS1 domain map supports this position. Flagged for human review: no named curated ROS1 domain/hotspot map was available.
PM2	Met	Met (Supporting): absent (AF = 0) from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, three independent population datasets. Per-position coverage at this site could not be independently verified.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	N/A	Not applicable: PM3 applies only to recessive disorders, and no recessive germline mechanism is established for ROS1.	generic_acmg_combination_rules clinvar pvs1_gene_context
PM4	N/A	Not applicable: this missense substitution produces no protein length change, which PM4 requires.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic variant at the same residue (p.Tyr2023) was identified for comparison.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no de novo occurrence or parental testing results were reported for this variant.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree or family segregation data exist for this variant.	clinvar generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no ROS1 missense-constraint data (e.g., gnomAD Z-score) were available.	pvs1_gene_context oncokb
PP3	Not met	Not met: SpliceAI max delta 0.01 predicts no splice impact, and REVEL 0.52 is uninformative (below 0.773, above 0.016).	spliceai revel bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no carrier phenotype or clinical case description was available for this variant.	oncokb generic_acmg_combination_rules
PP5	Not met	Not met: this variant has no ClinVar record, so no expert-panel pathogenic classification exists to support PP5.	clinvar generic_acmg_combination_rules
BA1	Not met	Not met: allele frequency is 0 in all queried population databases, far below the >5% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: absent (AF = 0) from population databases, so the frequency cannot exceed any disease-consistent threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: no healthy-adult carriers of this variant were observed in any population cohort.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional studies demonstrating a benign effect on protein function or splicing exist.	oncokb spliceai clinvar generic_acmg_combination_rules
BS4	Not assessed	Not assessed: no family segregation testing data exist for this variant.	clinvar generic_acmg_combination_rules
BP1	Not met	Not met: ROS1 disease is not limited to truncating variants; non-truncating alterations are disease-relevant.	pvs1_gene_context oncokb
BP2	Not assessed	Not assessed: no allele-phase (trans/cis) observation with a pathogenic variant exists for this variant. Flagged for human review: no external family or allele-phase data were available.	generic_acmg_combination_rules clinvar pvs1_gene_context
BP3	N/A	Not applicable: BP3 applies to in-frame indels in repeat regions, not missense substitutions.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: only SpliceAI (max delta 0.01) supports no impact, and REVEL 0.52 is uninformative, so the multiple-lines requirement fails.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband-level data exist to evaluate an alternative molecular basis for disease.	generic_acmg_combination_rules
BP6	Not met	Not met: this variant has no ClinVar record, so no expert-panel benign classification exists to support BP6.	clinvar generic_acmg_combination_rules
BP7	N/A	Not applicable: BP7 applies only to synonymous variants, and this is a missense substitution.	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.