ROS1c.6202_6203delLikely pathogenic

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Variant interpretation report

ROS1 c.6202_6203del, p.(Val2068LeufsTer15)

NM_002944.2:c.6202_6203del NP_002935.2:p.(Val2068LeufsTer15) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ROS1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic)
Expert rules: Not recorded
Pipeline record: 2 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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.
PM2 (moderate): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

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.

PM2Moderate

PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.040 maximum delta

Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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).

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.

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).

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴

Evidence considered

Frameshift deletion NM_002944.2:c.6202_6203del (p.Val2068LeufsTer15) in exon 39/43
PTC 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
familial lung cancer)

Still missing

No ClinGen CSPEC/VCEP for ROS1
PVS1 applied under generic PMC6185798 framework
Biologically relevant transcript confirmation should be verified by clinical laboratory

Sources

pvs1_generic_framework ↗gnomad_v2 ↗gnomad_v4 ↗

PM2 ModerateNM_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. Details ▾Hide ▴

Evidence considered

Absent from gnomAD v2.1 (AF=0)
Absent from gnomAD v4.1 (AF=0)
Absent from gnomAD-Canada v1.0 (AC=0
AN=0)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo observation with confirmed maternity and paternity is available for this variant. Details ▾Hide ▴

Still missing

No de novo data available

PS3 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. Details ▾Hide ▴

Evidence considered

OncoKB: Unknown Oncogenic Effect
no variant-specific functional data

Still missing

No functional studies available for this variant

Sources

oncokb ↗

PS4 No case-control data demonstrating statistically increased prevalence of this variant in affected individuals versus controls is available. Details ▾Hide ▴

Still missing

No affected-population data 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. Details ▾Hide ▴

Evidence considered

Not located in a statistically significant hotspot

PM6 No assumed de novo observation is available for this variant. No publications or database entries report de novo occurrence. Details ▾Hide ▴

Still missing

No de novo data available

PP1 No co-segregation data in affected family members is available for this variant. Details ▾Hide ▴

Still missing

No familial segregation data available

PP3 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score 0.04 — no significant splice impact predicted
REVEL/BayesDel not applicable (not SNV)

Still missing

No in silico missense prediction tools applicable to frameshift variants

Sources

spliceai ↗

PP4 No patient phenotype or family history information is provided. PP4 requires a phenotype highly specific for a disease with a single genetic etiology. Details ▾Hide ▴

Still missing

No patient phenotype provided

PP5 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. Details ▾Hide ▴

Evidence considered

Absent from ClinVar — no classification or reputable-source assertion available

Sources

clinvar ↗

BA1 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. Details ▾Hide ▴

Evidence considered

Allele frequency is 0.0 in all gnomAD datasets — does not meet BA1 threshold (>1%)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 The variant is absent from all population databases. Under non-VCEP rules, BS1 requires an allele frequency >0.3%, which is not met. Details ▾Hide ▴

Evidence considered

Allele frequency is 0.0 — does not meet BS1 threshold (>0.3%)

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

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. Details ▾Hide ▴

Still missing

No healthy-adult observation data available

BS3 No well-established in vitro or in vivo functional studies demonstrating no damaging effect are available for this variant. Details ▾Hide ▴

Still missing

No benign functional studies available

BS4 No lack of segregation data in affected family members is available for this variant. Details ▾Hide ▴

Still missing

No familial segregation data available

BP2 No evidence is available of this variant being observed in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴

Still missing

No phase data available

BP5 No evidence is available that this variant was found in a case with an alternative molecular basis for disease. Details ▾Hide ▴

Still missing

No alternate molecular basis data available

BP6 This variant is absent from ClinVar and has not been reported as benign by a reputable source. Details ▾Hide ▴

Evidence considered

Absent from ClinVar — no benign assertion available

Sources

clinvar ↗

PS5 No evidence is available that this variant was identified via single-gene testing after exclusion of alternative genetic causes. Details ▾Hide ▴

Still missing

No single-gene testing information available

Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped per adjudication instructions. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ABP4 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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta 0.04 — confirms absence of cryptic splice effect but does not mitigate protein-truncating impact

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: ROS1
Transcript: NM_002944.2
Coding (HGVS c.): NM_002944.2:c.6202_6203del
Protein (HGVS p.): NP_002935.2:p.(Val2068LeufsTer15)
GRCh38: chr6:117311049 GAC>G
GRCh37: chr6:117632212 GAC>G

Gene diagram

Every interpreted variant in ROS1, mapped onto the exon structure of NM_002944.2. Select a row to find it on the plot.

ROS1NM_002944.2

Fetching transcript structure from UCSC…

Exons

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Transcript span

—

Strand

—

Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in ROS1 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +68 bp

0.040

SpliceAI acceptor gainat -30 bp

0.020

SpliceAI donor lossat -29 bp

0.020

SpliceAI donor gainat -93 bp

0.040

Pangolin splice lossmagnitude shown

-0.110

Pangolin splice gain

0.100

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta score 0.04 — no significant splice impact predicted
REVEL/BayesDel not applicable (not SNV)

Still missing

No in silico missense prediction tools applicable to frameshift variants

Sources

spliceai ↗

Evidence considered

SpliceAI max delta 0.04 — confirms absence of cryptic splice effect but does not mitigate protein-truncating impact

Sources

spliceai ↗

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a frameshift deletion. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.040 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

Functional

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.