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ROS1 encodes a transmembrane receptor protein with intracellular tyrosine kinase activity, belonging to the sevenless subfamily of tyrosine kinase insulin receptor genes. It is a proto-oncogene highly expressed in a variety of tumor cell lines and may normally function as a growth or differentiation factor receptor, though its physiological role and ligand in humans are not yet known. ROS1 gene rearrangements that retain the kinase domain are implicated in several human epithelial cancers, most commonly non-small cell lung cancer, as well as cholangiocarcinoma, ovarian carcinoma, gastric carcinoma, and angiosarcoma, and are thought to drive tumor development through constitutive kinase activation.
This variant
ROS1 is a proto-oncogene whose kinase-domain rearrangements drive several cancers, most commonly non-small cell lung cancer. This missense variant (p.Tyr2023Phe), located in the tyrosine kinase region, is absent from population databases and has no reported clinical or functional evidence, so its contribution to ROS1-related cancer risk is currently uncertain (VUS).
Transcript
NM_002944.2
HGVS · transcript:coding
NM_002944.2:c.6068A>T
GRCh38
chr6:117317210 T>A
GRCh37
chr6:117638373 T>A
VUS: with no ROS1 CSPEC/VCEP, the generic ACMG/AMP 2015 framework applies; the only met criterion, PM2 (Supporting, AF = 0 in gnomAD v2.1, v4.1, and gnomAD-Canada v1.0), satisfies no combination rule.
Classification rationale
PM2VUS
ROS1 c.6068A>Tmissense
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.
PM2→VUS
LYFE Sciences is an AI system, and it can make mistakes. Criteria
may be applied incorrectly, sources may be misread, and a confident-looking
classification can still be wrong. Double-check every criterion and
its underlying evidence before relying on any call.
Gene diagram
· NM_002944.2 · variants mapped to exon structure
ROS1NM_002944.2
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ROS1—click a row to locate it on the plot · use the link column to open its page
Protein
Location
Classification
Link
Applied criteria · 1 applied · 22 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 1
Strength Supporting Moderate Strong Very strong
✓
PM2supportingPathogenic
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.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ROS1, a receptor tyrosine kinase, is altered by mutation or chromosomal rearrangement in a diverse range of cancers, including lung cancer.
