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.1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.2 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.3 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.4 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).5
ROS1
Final classification
VUS
ROS1 c.6100C>T · p.Leu2034Phe
ROS1
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PP3 supporting; combination = 2 supporting, which maps to VUS.
Classification rationale
PM2PP3
VUS
ROS1 c.6100C>T
PM2 + PP3
→
VUS
1
pvs1_variant_assessment
3
revelbayesdel
5
generic_acmg_combination_rules
Gene diagram
· NM_002944.2 · variants mapped to exon structure
ROS1
NM_002944.2
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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).
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).Absent from gnomAD-Canada v1.0 (genomes).
✓
PP3
supporting
Pathogenic
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: 0.918 (deleterious).BayesDel: 0.34143 (deleterious).
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant with the same amino acid change (p.Leu2034Phe) at this codon has been reported in ClinVar or the literature.
PS2
No de novo occurrence data with confirmed maternity and paternity available for this variant in ClinVar or the literature.
PS3
No variant-specific functional studies identified.
PS4
No case-control studies or statistical enrichment data available.
PM1
This variant does not lie in a statistically significant hotspot per cancerhotspots.org.
PM5
No pathogenic missense variants at the same amino acid residue (Leu2034) identified in ClinVar.
PM6
No de novo occurrence data (without confirmed maternity and paternity) available in ClinVar or the literature.
PP1
No cosegregation data with disease in multiple affected family members available.
PP2
HCI prior not available for ROS1.
PP4
No patient phenotype or family history information is available to assess specificity for a disease with a single genetic etiology.
PP5
Variant is absent from ClinVar; no reputable source has reported this variant as pathogenic.
Benign
BA1
Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
Variant is absent from gnomAD.
BS2
No data on healthy adult carriers.
BS3
No in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant.
BS4
No segregation data in affected family members available; no evidence of lack of segregation.
BP1
Insufficient evidence to determine that only truncating variants cause ROS1-related disease.
BP2
No data on observations in trans with a pathogenic variant or in cis with a pathogenic variant.
BP4
REVEL score of 0.918 predicts a deleterious effect, and BayesDel (0.34143) also exceeds the pathogenicity threshold.
BP5
No alternate molecular basis for disease has been identified in cases harboring this variant.
BP6
Variant is absent from ClinVar; no reputable source has reported this variant as benign.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.918. BayesDel score = 0.34143.
Functional
Unknown Oncogenic Effect
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.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links