About ROS1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ROS1 c.6565G>T, p.(Asp2189Tyr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with rarity in the general population (allele frequency below 0.1% threshold).
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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 moderate; combination = 1 moderate, which maps to VUS.
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.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. 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 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.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 22 not met · 1 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002944.2:c.6565G>T (p.Asp2189Tyr) in ROS1 is a missense variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at moderate strength.
This variant does not meet PVS1 criteria as it is a missense substitution, not a null variant eligible under the ClinGen SVI PVS1 decision tree (PMC6185798).
In silico predictions are conflicting: REVEL score of 0.589 is borderline, BayesDel score of -0.169 suggests a benign effect, and SpliceAI predicts no splice impact (max delta 0.02). Neither PP3 nor BP4 is met.
No functional studies, ClinVar classifications, case-control data, segregation data, or literature reports are available for this variant. No criterion beyond PM2 is met.
Overall, the evidence is insufficient for classification. With only PM2 (moderate) met and no other criteria satisfied, this variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines (PMID:25741868).
No criteria match.
Met · 1
PM2 ModerateThis variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with rarity in the general population (allele frequency below 0.1% threshold). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles).
- Absent from gnomAD v4.1 (0 alleles).
- Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No same amino acid change (p.Asp2189Tyr) has been reported as pathogenic in ClinVar or the literature. The variant has no ClinVar entries and no publications describe this amino acid substitution. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no known pathogenic variant at Asp2189.
Sources
PS2 No de novo observation has been reported for this variant in any publication or database. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No parental or trio data available.
PS3 No functional studies have been performed on this variant. OncoKB reports Unknown Oncogenic Effect and no publications with variant-specific functional data were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No variant-specific functional studies identified in literature or databases.
Still missing
- No in vitro or in vivo functional data for p.Asp2189Tyr.
Sources
PS4 No case-control data are available. The variant is absent from ClinVar and no affected individuals have been reported. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reported cases.
Still missing
- No case-control or prevalence data available.
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. No evidence was identified that residue Asp2189 resides in a critical well-established functional domain without benign variation, based on available case evidence. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed. No domain-level functional characterization for Asp2189 in case evidence.
Still missing
- No domain-level characterization for Asp2189 in the available evidence.
PM5 No pathogenic missense variant at the same amino acid residue (Asp2189) has been identified. PM5 candidate search found no same-residue comparators in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates found
- no expert-panel P/LP comparator at Asp2189.
Still missing
- No pathogenic variants at Asp2189 identified in ClinVar.
Sources
pm5_candidates
PM6 No de novo observation has been reported for this variant. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No de novo or trio testing data.
PP1 No cosegregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No family or segregation data available.
Still missing
- No segregation analysis performed.
PP2 HCI Prior data are not available for ROS1 (gene not supported by the predictor). No constraint metrics or missense Z-score are available to assess whether ROS1 has a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
- HCI Prior: gene not supported. No constraint or Z-score data available in case evidence.
Still missing
- No missense constraint metrics for ROS1 available.
PP3 In silico predictions are conflicting: REVEL score of 0.589 is in the borderline range (not clearly pathogenic), BayesDel score of -0.169 suggests a benign effect, and SpliceAI max delta score of 0.02 predicts no splice impact. Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.589 (borderline
- not clearly pathogenic).
- BayesDel: -0.169 (benign range
- scores >0 indicate damaging).
- SpliceAI: max delta 0.02 (no predicted splice impact).
Sources
PP5 No reputable source has reported this variant as pathogenic. It is absent from ClinVar and OncoKB provides no pathogenic classification. ClinVar 3-star expert panel classification is not available. Details ▾Hide ▴
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: allele frequency 0%.
- gnomAD v4.1: allele frequency 0%.
- gnomAD-Canada: allele frequency 0%.
Sources
BS1 The variant is absent from gnomAD. Allele frequency is 0%, well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: allele frequency 0%.
- gnomAD v4.1: allele frequency 0%.
Sources
BS2 No data are available regarding observation of this variant in healthy adults at an age when full penetrance of a ROS1-related disorder would be expected. Details ▾Hide ▴
Evidence considered
- No healthy-adult observation data available.
Still missing
- No population-specific penetrance data.
BS3 No functional studies have been performed on this variant demonstrating a neutral or benign effect. Details ▾Hide ▴
Evidence considered
- No variant-specific functional studies available.
Still missing
- No in vitro or in vivo functional data.
BS4 No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
- No family or segregation data available.
Still missing
- No segregation analysis performed.
BP1 ROS1 encodes a receptor tyrosine kinase. Missense variants in kinase domains are a recognized disease mechanism for receptor tyrosine kinases. BP1 (missense variant in gene where primarily truncating variants cause disease) does not apply. Details ▾Hide ▴
Evidence considered
- ROS1 is a receptor tyrosine kinase
- missense variants in kinase domains are an established disease mechanism.
BP2 No data are available on observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No trans-phase observation data available.
Still missing
- No allelic phase data.
BP4 In silico predictions are conflicting: REVEL 0.589 is borderline (not clearly benign), BayesDel -0.169 suggests a benign effect, and SpliceAI 0.02 shows no splice impact. Multiple lines of computational evidence do not consistently suggest no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.589 (borderline
- not clearly benign).
- BayesDel: -0.169 (benign range).
- SpliceAI: max delta 0.02 (no splice impact).
Sources
BP5 No alternate molecular basis for disease has been identified in a case carrying this variant. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No data on alternate molecular diagnoses.
BP6 No reputable source has reported this variant as benign. It is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification from any source.
Sources
Not assessed · 1 · no assessment recorded
PP4 No patient phenotype or clinical data were provided for this case. PP4 cannot be assessed without knowing whether the patient's presentation is highly specific for a ROS1-related disorder. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available in case materials.
Still missing
- Patient phenotype and family history not provided.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002944.2:c.6565G>T is a missense variant (p.Asp2189Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework (PMC6185798) applies only to null variants. Details ▾Hide ▴
Evidence considered
- Missense substitution at c.6565G>T (p.Asp2189Tyr)
- variant_bucket 'other' does not qualify for PVS1 under the ClinGen SVI PVS1 decision tree.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ARequires observation in trans with a pathogenic variant; no such data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AProtein length change criterion; variant is a missense substitution, not an in-frame deletion/insertion or stop-loss. Details ▾Hide ▴
No further detail was recorded.
BP3 N/AIn-frame deletion/insertion criterion; variant is a substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ASynonymous variant criterion; NM_002944.2:c.6565G>T is a missense substitution (p.Asp2189Tyr). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- ROS1
- Transcript
- NM_002944.2
- Coding (HGVS c.)
- NM_002944.2:c.6565G>T
- Protein (HGVS p.)
- NP_002935.2:p.(Asp2189Tyr)
- GRCh38
- chr6:117308798 C>A
- GRCh37
- chr6:117629961 C>A
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
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ROS1
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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
Other predictors
- REVEL
- 0.589
- BayesDel
- -0.169
How the predictions were used
PP3 In silico predictions are conflicting: REVEL score of 0.589 is in the borderline range (not clearly pathogenic), BayesDel score of -0.169 suggests a benign effect, and SpliceAI max delta score of 0.02 predicts no splice impact. Multiple lines of computational evidence do not consistently support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.589 (borderline
- not clearly pathogenic).
- BayesDel: -0.169 (benign range
- scores >0 indicate damaging).
- SpliceAI: max delta 0.02 (no predicted splice impact).
Sources
BP4 In silico predictions are conflicting: REVEL 0.589 is borderline (not clearly benign), BayesDel -0.169 suggests a benign effect, and SpliceAI 0.02 shows no splice impact. Multiple lines of computational evidence do not consistently suggest no impact on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.589 (borderline
- not clearly benign).
- BayesDel: -0.169 (benign range).
- SpliceAI: max delta 0.02 (no splice impact).
Sources
BP7 N/ASynonymous variant criterion; NM_002944.2:c.6565G>T is a missense substitution (p.Asp2189Tyr). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.589. BayesDel score = -0.169433.
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 0.020
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_002944.2%3Ac.6565G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-117629961-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-117308798-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-117308798-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002944.2%3Ac.6565…
- OncoKB ↗www.oncokb.org/gene/ROS1/D2189Y
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ROS1+c.6565G%3ET
- Cancer hotspots ↗www.cancerhotspots.org/
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 = 0.02). REVEL score = 0.589. BayesDel score = -0.169433.
Functional
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.
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.