Variant classification summary

NM_001378902.1:c.6076G>A

ROS1 · NP_001365831.1:p.(Gly2026Arg) · NM_001378902.1

GRCh37: chr6:117638347 C>T · GRCh38: chr6:117317184 C>T

Gene: ROS1 Transcript: NM_001378902.1

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ROS1

Transcript

NM_001378902.1

Protein

NP_001365831.1:p.(Gly2026Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 supporting reflects absence from gnomAD v2.1 and v4.1.

2

VUS: PP3 supporting reflects REVEL 0.862 exceeding the generic missense threshold of 0.644.

Final determination: Under generic ACMG/AMP 2015 fallback rules, PM2 supporting plus PP3 supporting is insufficient for a pathogenic, likely pathogenic, benign, or likely benign call, so the final classification is 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 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no validated previously established pathogenic variant with the same p.Gly2026Arg amino-acid change was identified.	clinvar PMID:23562183 PMID:24627688 PMID:29355391 PMID:29398453
PS2	Not assessed	Not assessed: No documented germline proband result, parental testing, or confirmed maternity and paternity is available for this de novo criterion.	clinvar
PS3	Not assessed	Not assessed: no validated variant-specific functional assay or reproducible damaging-effect result was identified for ROS1 p.Gly2026Arg.	PMID:23562183 PMID:24627688 PMID:29355391 PMID:29398453
PS4	Not met	Not met: the only PS4 literature candidate did not mention ROS1 p.Gly2026Arg or provide affected/control counts, OR, RR, or confidence interval.	PMID:24627688
PM1	Not assessed	Not assessed: no qualifying ROS1 hotspot or critical functional domain with absent benign variation was established for residue 2026.	hotspots cosmic
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, corresponding to observed frequency 0 versus the <=0.0001 PM2 threshold.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected-proband second pathogenic allele or parental/offspring testing establishes a pathogenic variant in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: the PM5 candidate review found zero validated different missense pathogenic comparators at residue 2026.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: No germline de novo observation is documented, and the available exact-variant ClinVar submission is explicitly somatic.	clinvar
PP1	Not assessed	Not assessed: No affected relatives, informative meioses, or variant-specific segregation data are documented for this family.
PP2	Not assessed	Not assessed: no gene-level evidence establishes both low benign missense variation and a common disease-causing missense mechanism for ROS1.	gnomad_v2 gnomad_v4
PP3	Met	Met at supporting: REVEL 0.862 exceeds the generic PP3 supporting threshold of 0.644 for this missense variant.	revel
PP4	Not assessed	Not assessed: lung adenocarcinoma is recorded, but detailed phenotype or family-history evidence showing a highly specific single-gene disorder is unavailable.	clinvar
PP5	Not met	Not met: ClinVar has one non-expert laboratory Pathogenic submission, while the reviewed candidate paper does not mention this exact ROS1 variant.	clinvar PMID:24627688
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no allele frequency or grpmax FAF reaching the 0.05 BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 show no allele frequency or grpmax FAF above the generic 0.01 BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports the variant absent but provides no observed healthy adult carrier or homozygote/hemizygote required for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated variant-specific assay demonstrated that ROS1 p.Gly2026Arg has no damaging effect on protein function or splicing.	PMID:23562183 PMID:24627688 PMID:29355391 PMID:29398453
BS4	Not assessed	Not assessed: No tested affected relatives or family genotype-phenotype data demonstrate lack of segregation.
BP1	Not assessed	Not assessed: no validated ROS1 disease variant spectrum shows that primarily truncating variants, rather than missense variants, cause disease.
BP2	Not assessed	Not assessed: no individual-level observation or phase testing shows this variant in trans or cis with a pathogenic variant.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.862 is above the generic BP4 supporting threshold of 0.29, and the SpliceAI score is not applicable to missense BP4.	revel
BP5	Not assessed	Not assessed: no alternate molecular diagnosis or second disease-causing molecular basis is documented for the case.
BP6	Not met	Not met: the exact-variant ClinVar record is a non-expert Pathogenic submission, with no benign or Likely benign reputable-source classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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