NM_002944.2:c.6100C>T

ROS1 · NP_002935.2:p.(Leu2034Phe) · NM_002944.2

GRCh37: chr6:117638341 G>A · GRCh38: chr6:117317178 G>A

Gene: ROS1 Transcript: NM_002944.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ROS1

Transcript

NM_002944.2

Protein

NP_002935.2:p.(Leu2034Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002944.2:c.6100C>T (p.Leu2034Phe) is a missense variant in exon 38 of ROS1, encoding a residue within the kinase domain of this receptor tyrosine kinase.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.

REVEL score of 0.918 predicts a deleterious effect, and BayesDel score of 0.34143 exceeds the threshold for pathogenicity, meeting PP3 at supporting strength.

The variant is absent from ClinVar and has not been reported in the published literature. No functional studies, de novo reports, cosegregation data, or case-control analyses are available.

With only two supporting criteria (PM2_Supporting + PP3_Supporting), the evidence is insufficient for classification as likely pathogenic or likely benign under the ACMG/AMP 2015 framework. This variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	Missense variant (c.6100C>T, p.Leu2034Phe) does not meet PVS1 null variant criteria per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is restricted to nonsense, frameshift, canonical ±1/2 splice consensus, initiation codon, and exon deletion variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Leu2034Phe) at this codon has been reported in ClinVar or the literature.	clinvar
PS2	Not met	No de novo occurrence data with confirmed maternity and paternity available for this variant in ClinVar or the literature.	clinvar
PS3	Not met	No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect for ROS1 L2034F. No publications with functional characterization of this variant were found.	oncokb
PS4	Not met	No case-control studies or statistical enrichment data available. Variant is absent from gnomAD, precluding odds ratio calculation.	gnomad_v2 gnomad_v4
PS5	Not met	No established pathogenic missense variant at codon 2034 identified in ClinVar. The variant is absent from ClinVar entirely.	clinvar
PM1	Not met	This variant does not lie in a statistically significant hotspot per cancerhotspots.org. While position 2034 falls within the kinase domain of ROS1, no variant-specific domain-level functional characterization or established mutational hotspot has been demonstrated at this residue.
PM2	Met	Variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant (allele frequency <0.1% in all populations).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variants at the same amino acid residue (Leu2034) identified in ClinVar. PM5 candidate harvesting returned zero same-residue candidates.	pm5_candidates
PM6	Not met	No de novo occurrence data (without confirmed maternity and paternity) available in ClinVar or the literature.	clinvar
PP1	Not met	No cosegregation data with disease in multiple affected family members available.
PP2	Not met	HCI prior not available for ROS1. While ROS1 is a receptor tyrosine kinase with described germline variants, no gene-level missense constraint metrics (e.g., Z-score) are available to demonstrate a low rate of benign missense variation.
PP3	Met	REVEL score of 0.918 predicts a deleterious effect (threshold >0.75). BayesDel score of 0.34143 also exceeds the pathogenicity threshold (>0.27). Multiple lines of computational evidence support a deleterious effect on the protein.	revel bayesdel
PP4	Not met	No patient phenotype or family history information is available to assess specificity for a disease with a single genetic etiology.
PP5	Not met	Variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.	clinvar oncokb
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the 1% BA1 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD. Allele frequency is well below the >0.3% BS1 threshold for non-VCEP assessment.	gnomad_v2 gnomad_v4
BS2	Not met	No data on healthy adult carriers. Variant is absent from all population databases.	gnomad_v2 gnomad_v4
BS3	Not met	No in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant.	oncokb
BS4	Not met	No segregation data in affected family members available; no evidence of lack of segregation.
BP1	Not met	Insufficient evidence to determine that only truncating variants cause ROS1-related disease. Published literature reports both truncating and missense variants in ROS1 (PMID:32906649). BP1 cannot be applied.
BP2	Not met	No data on observations in trans with a pathogenic variant or in cis with a pathogenic variant.
BP4	Not met	REVEL score of 0.918 predicts a deleterious effect, and BayesDel (0.34143) also exceeds the pathogenicity threshold. Computational evidence does not support a benign interpretation.	revel bayesdel
BP5	Not met	No alternate molecular basis for disease has been identified in cases harboring this variant.
BP6	Not met	Variant is absent from ClinVar; no reputable source has reported this variant as benign.	clinvar
BP7	N/A	Variant is a missense change (c.6100C>T, p.Leu2034Phe), not a synonymous (silent) variant. BP7 is restricted to synonymous variants with no predicted splice impact and low nucleotide conservation.

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.