NM_002944.2:c.6202_6203del is a frameshift deletion predicted to result in a premature termination codon (p.Val2068LeufsTer15) in exon 39 of 43, expected to undergo nonsense-mediated decay, qualifying for PVS1 at very_strong strength under the ClinGen SVI PVS1 framework (PMC6185798).1 Germline loss-of-function is supported as a disease mechanism for ROS1, with literature linking ROS1 truncating variants to hereditary breast cancer (PMID:32906649) and familial lung cancer susceptibility (PMID:41390056). The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0), meeting PM2 at moderate strength under generic ACMG/AMP population frequency thresholds.2 No additional pathogenic or benign criteria are met. PVS1 (very_strong) plus PM2 (moderate) classifies this variant as Likely Pathogenic under generic ACMG/AMP 2015 final combination rules (PMID:25741868).3
ROS1
Final classification
Likely Pathogenic
ROS1 c.6202_6203del · p.Val2068LeufsTer15
ROS1
NM_002944.2:c.6202_6203del is a frameshift deletion predicted to result in a premature termination codon (p.Val2068LeufsTer15) in exon 39 of 43, expected to undergo nonsense-mediated decay, qualifying for PVS1 at very_strong strength under the ClinGen SVI PVS1 framework (PMC6185798).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
ROS1 c.6202_6203del
PVS1 + PM2
→
Likely Pathogenic
Gene diagram
· NM_002944.2 · variants mapped to exon structure
ROS1
NM_002944.2
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
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 = 0.04).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
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