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
PVS1PM2
ROS1
c.6202_6203del
p.Val2068LeufsTer15
This variant
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 applied · 17 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 · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
NM_002944.2:c.6202_6203del is a frameshift deletion predicted to cause a premature termination codon at p.Val2068LeufsTer15 in exon 39 of 43, expected to trigger nonsense-mediated decay. Germline loss-of-function is a recognized disease mechanism for ROS1, with supporting literature linking ROS1 truncating variants to hereditary breast cancer and familial lung cancer susceptibility (PMIDs: 32906649, 41390056). Under the ClinGen SVI PVS1 framework (PMC6185798), a frameshift variant predicted to undergo NMD in a gene with established LOF mechanism qualifies for PVS1 at very_strong strength.
Frameshift deletion NM_002944.2:c.6202_6203del (p.Val2068LeufsTer15) in exon 39/43PTC at codon 2083 predicted to undergo nonsense-mediated decay (not in last exon)ROS1 loss-of-function established as germline disease mechanism via literature (hereditary breast cancer
✓
PM2
moderate
Pathogenic
NM_002944.2:c.6202_6203del is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, with an allele frequency of 0.0 in all population databases. Under generic ACMG/AMP rules (non-VCEP cutoff: <0.1%), this supports PM2 at moderate strength.
Absent from gnomAD v2.1 (AF=0)Absent from gnomAD v4.1 (AF=0)Absent from gnomAD-Canada v1.0 (AC=0
Assessed · not applied
· 17 not met · 0 not assessed
Pathogenic
PS2
No de novo observation with confirmed maternity and paternity is available for this variant.
PS3
No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified for NM_002944.2:c.6202_6203del.
PS4
No case-control data demonstrating statistically increased prevalence of this variant in affected individuals versus controls is available.
PM1
This variant does not lie within a statistically significant mutational hotspot (Cancer Hotspots database), and no established ROS1 functional domain has been demonstrated to be a germline pathogenic hotspot for this residue.
PM6
No assumed de novo observation is available for this variant.
PP1
No co-segregation data in affected family members is available for this variant.
PP3
No multiple lines of computational evidence support a deleterious effect.
PP4
No patient phenotype or family history information is provided.
PP5
This variant is absent from ClinVar and has not been reported as pathogenic by a reputable source.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0).
BS1
The variant is absent from all population databases.
BS2
No evidence is available of this variant being observed in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS3
No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4
No lack of segregation data in affected family members is available for this variant.
BP2
No evidence is available of this variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant.
BP5
No evidence is available that this variant was found in a case with an alternative molecular basis for disease.
BP6
This variant is absent from ClinVar and has not been reported as benign by a reputable source.
N/A · 9
PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP4 · BP7
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