LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-07-02
Case ID: NM_002944.2_c.6202_6203delGT_20260702_200438
Framework: ACMG/AMP 2015
Variant classification summary

NM_002944.2:c.6202_6203delGT

ROS1  · NP_002935.2:p.(Val2068LeufsTer15)  · NM_002944.2
GRCh37: chr6:117632212 GAC>G  ·  GRCh38: chr6:117311049 GAC>G
Gene: ROS1 Transcript: NM_002944.2
Final call
Likely Pathogenic
PVS1 very strong PM2 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
ROS1
Transcript
NM_002944.2
Protein
NP_002935.2:p.(Val2068LeufsTer15)
gnomAD AF
ClinVar
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
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).
2
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).
3
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.
4
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).
Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.
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 Met 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.
pvs1_generic_framework gnomad_v2 gnomad_v4
PS1 N/A PS1 applies to nucleotide changes producing the same amino acid change as an established pathogenic missense variant. This variant is a frameshift deletion, not a missense substitution.
PS2 Not met No de novo observation with confirmed maternity and paternity is available for this variant.
PS3 Not met No well-established in vitro or in vivo functional studies demonstrating a damaging effect were identified for NM_002944.2:c.6202_6203del. OncoKB classifies this alteration as 'Unknown Oncogenic Effect.' No publications mention the variant in a functional context.
oncokb
PS4 Not met No case-control data demonstrating statistically increased prevalence of this variant in affected individuals versus controls is available.
PS5 Not met No evidence is available that this variant was identified via single-gene testing after exclusion of alternative genetic causes.
PM1 Not met 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.
PM2 Met 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.
gnomad_v2 gnomad_v4 gnomad_canada
PM3 N/A Skipped per adjudication instructions.
PM4 N/A PM4 applies to in-frame deletions/insertions in non-repeat regions or stop-loss variants. This is a frameshift deletion; the protein-truncating effect is captured by PVS1.
PM5 N/A PM5 applies to a novel missense change at a residue where a different pathogenic missense change has been established. This is a frameshift deletion, not a missense variant. PM5 residue-level semantics cannot be resolved for a frameshift.
PM6 Not met No assumed de novo observation is available for this variant. No publications or database entries report de novo occurrence.
PP1 Not met No co-segregation data in affected family members is available for this variant.
PP2 N/A PP2 applies to missense variants in genes with a low rate of benign missense variation where missense is a common disease mechanism. This variant is a frameshift deletion, not a missense variant.
PP3 Not met No multiple lines of computational evidence support a deleterious effect. REVEL and BayesDel scores are unavailable for this non-SNV variant. SpliceAI predicts no significant splice impact (max delta score 0.04). The variant's deleterious effect is via protein truncation, which is addressed by PVS1.
spliceai
PP4 Not met No patient phenotype or family history information is provided. PP4 requires a phenotype highly specific for a disease with a single genetic etiology.
PP5 Not met This variant is absent from ClinVar and has not been reported as pathogenic by a reputable source. No expert panel classification exists for this variant.
clinvar
BA1 Not met The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency 0.0). BA1 requires an allele frequency >1% in population databases.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met The variant is absent from all population databases. Under non-VCEP rules, BS1 requires an allele frequency >0.3%, which is not met.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not met 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 Not met No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant.
BS4 Not met No lack of segregation data in affected family members is available for this variant.
BP1 N/A BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant.
BP2 Not met No evidence is available of this variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant.
BP3 N/A BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift deletion.
BP4 N/A BP4 applies to variants with multiple lines of computational evidence suggesting no impact. SpliceAI shows no significant splice effect (delta 0.04), but this is a frameshift variant whose primary mechanism is protein truncation, which is captured by PVS1 at very_strong strength. The absence of splicing impact does not constitute independent benign evidence for a truncating variant.
spliceai
BP5 Not met No evidence is available that this variant was found in a case with an alternative molecular basis for disease.
BP6 Not met This variant is absent from ClinVar and has not been reported as benign by a reputable source.
clinvar
BP7 N/A BP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion.
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