About ROS1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ROS1 c.6609C>A, p.(Asp2203Glu)
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present in gnomAD v4.1 at an extremely low allele frequency (2.50×10⁻⁶; 4/1,600,906 alleles; 0 homozygotes; grpmax FAF=6.8×10⁻⁷), well below the 0.1% PM2 threshold for population-level absence. This low frequency in control populations provides supporting evidence for pathogenicity.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.14 (benign-leaning), BayesDel score is −0.455671 (predicted benign), and SpliceAI predicts no splice alteration (max delta = 0.01). Additionally, the amino acid substitution is conservative (Asp→Glu; both are acidic residues with similar biochemical properties), further supporting a neutral effect.
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 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, 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
4 / 1,600,906 alleles
gnomAD v4.1: 4 / 1,600,906 alleles. Recorded AF 2.49859e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
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.
27 criteria with recorded statuses: 2 met · 8 not met · 0 not assessed · 17 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.6609C>A (p.Asp2203Glu) is a rare missense variant in ROS1, present in gnomAD v4.1 at extremely low frequency (AF=2.50×10⁻⁶, 4/1,600,906 alleles, 0 homozygotes) and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting level.
Multiple in silico tools predict a benign effect: REVEL score is 0.14, BayesDel score is −0.455671, and SpliceAI predicts no splice impact (max delta=0.01). Additionally, the substitution is biochemically conservative (Asp→Glu, both acidic residues), meeting BP4 at supporting level.
This variant is absent from ClinVar with no clinical assertions, has not been reported in COSMIC, does not lie in a statistically significant mutational hotspot, and has no variant-specific functional evidence (OncoKB: Unknown Oncogenic Effect). No publications mention this specific variant.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced. No other criteria are met. This variant is classified as a Variant of Uncertain Significance (VUS) under ACMG/AMP 2015 generic framework.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v2.1 and gnomAD-Canada, and is present in gnomAD v4.1 at an extremely low allele frequency (2.50×10⁻⁶; 4/1,600,906 alleles; 0 homozygotes; grpmax FAF=6.8×10⁻⁷), well below the 0.1% PM2 threshold for population-level absence. This low frequency in control populations provides supporting evidence for pathogenicity. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent
- gnomAD v4.1: AF=2.50×10⁻⁶ (4/1
- 600
- 906 alleles
- 0 homozygotes)
- gnomAD-Canada v1.0: absent
- grpmax FAF=6.8×10⁻⁷
Sources
BP4 SupportingMultiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.14 (benign-leaning), BayesDel score is −0.455671 (predicted benign), and SpliceAI predicts no splice alteration (max delta = 0.01). Additionally, the amino acid substitution is conservative (Asp→Glu; both are acidic residues with similar biochemical properties), further supporting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.14 (low
- benign range)
- BayesDel: −0.455671 (predicted benign)
- SpliceAI max delta: 0.01 (no splice impact)
- Conservative substitution: Asp2203→Glu (both acidic
- similar size)
Sources
Not met · 8 · evaluated, threshold not reached
PS3 No well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. No publications mention this variant. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- No variant-specific functional studies identified in literature
Still missing
- No functional studies available
Sources
PS4 No case-control or cohort data support enrichment of this variant in affected individuals. The variant is absent from ClinVar with no clinical assertions. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no clinical assertions or submitter classifications
- gnomAD v4.1: 4 alleles among 1
- 600
- 906 (no case-control comparison available)
Still missing
- No case-control studies available
Sources
PM1 This variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org). The p.Asp2203Glu substitution is a conservative amino acid change (both acidic residues) located in the C-terminal region of ROS1 (exon 43 of 43), distal to the tyrosine kinase domain core. No evidence supports this residue as a critical functional domain with absence of benign variation. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not significant
- exact variant not listed
- Conservative substitution (Asp→Glu
- both negatively charged)
- Located at C-terminal residue 2203
- outside tyrosine kinase domain core (residues ~1945–2206)
PP3 Multiple in silico prediction tools uniformly predict a benign effect. REVEL score is 0.14 (well below 0.5 threshold), BayesDel score is −0.455671 (negative = predicted benign), and SpliceAI delta score is 0.01 (no predicted splice impact). No computational tool supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.14 (benign-leaning)
- BayesDel: −0.455671 (predicted benign)
- SpliceAI max delta: 0.01 (no splice impact)
Sources
PP4 No patient phenotype or clinical data are available for this variant. Absent from ClinVar with no clinical assertions. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no phenotype data available
Still missing
- No clinical phenotype data available
Sources
BA1 Allele frequency in gnomAD v4.1 is 0.00025% (2.50×10⁻⁶), well below the 1% BA1 threshold. This variant is not a common polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.00025%
- far below BA1 threshold of >1%
Sources
BS1 Allele frequency in gnomAD v4.1 is 0.00025% (2.50×10⁻⁶), below the 0.3% BS1 threshold. The variant is not observed at a frequency greater than expected for the disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.00025%
- below BS1 threshold of >0.3%
Sources
BS3 No well-established in vitro or in vivo functional studies demonstrate no damaging effect on protein function or splicing. While computational tools predict a benign effect, this alone is insufficient to meet BS3 without experimental functional data. Details ▾Hide ▴
Still missing
- No functional studies demonstrating no damaging effect
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002944.2:c.6609C>A is a missense variant (p.Asp2203Glu). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants; PVS1 is not applicable to this variant class. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution (p.Asp2203Glu
- exon 43/43)
- Not a null variant: not nonsense
- frameshift
- or canonical splice site variant
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/ANo prior pathogenic or likely pathogenic classification exists for a different nucleotide change at c.6609 producing the same amino acid substitution (p.Asp2203Glu). Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no alternate nucleotide change at this codon with a pathogenic classification identified
Sources
PS2 N/ANo de novo data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic or likely pathogenic missense comparator identified at residue Asp2203. The automated PM5 candidate harvest confirmed zero same-residue candidates in ClinVar. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json: 0 same-residue candidate variants
- recommendation level: not_applicable
Sources
pm5_candidates
PM6 N/ANo de novo data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP1 N/ANo co-segregation data available for this variant. Details ▾Hide ▴
No further detail was recorded.
PP2 N/AWhile ROS1 has emerging literature-based support for germline disease (familial lung cancer risk, hereditary breast cancer), the gene-level constraint metrics are unavailable (HCI prior not found) and the germline disease mechanism is not sufficiently established to apply PP2 in the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
- HCI prior: not found (gene not supported)
- No ClinGen gene-disease validity curation available for ROS1
Still missing
- No gene-level missense constraint score available
PP5 N/ANo evidence applicable; PP5 is not assessed. Details ▾Hide ▴
No further detail was recorded.
BS2 N/ANo data available on observation of this variant in healthy adult controls for a fully penetrant disorder. Details ▾Hide ▴
Still missing
- No healthy control observation data available
BS4 N/ANo co-segregation data available to demonstrate lack of segregation with disease. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. ROS1 has literature-based support for LOF as a germline disease mechanism (PMID:41390056, PMID:32906649), so the premise of BP1 is not met — truncating variants are not the sole established disease mechanism. Details ▾Hide ▴
Evidence considered
- ROS1 LOF is supported as a germline disease mechanism
- BP1 premise not satisfied
Sources
pvs1_gene_context
BP2 N/ANo data available on observation in trans with a pathogenic variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per instruction: variant type is substitution, not in-frame indel in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP5 N/ANo evidence applicable; BP5 is not assessed. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ANo evidence applicable; BP6 is not assessed. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_002944.2:c.6609C>A is a missense variant (p.Asp2203Glu), not a synonymous variant. BP7 (synonymous variant with no predicted splice impact) does not apply. Details ▾Hide ▴
Evidence considered
- Variant class: missense
- not synonymous
PS5 N/ANo evidence applicable; PS5 is not assessed. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- ROS1
- Transcript
- NM_002944.2
- Coding (HGVS c.)
- NM_002944.2:c.6609C>A
- Protein (HGVS p.)
- NP_002935.2:p.(Asp2203Glu)
- GRCh38
- chr6:117301098 G>T
- GRCh37
- chr6:117622261 G>T
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
—
Transcript span
—
Strand
—
Variants mapped
—
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
4 / 1,600,906 alleles
AF 2.5e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,600,906 alleles · 0 hom · FAF 6.8e-07
| African/African American1 / 74,596 | 1.3e-05 |
| European (non-Finnish)3 / 1,174,998 | 2.6e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.49859e-06; MAF= 0.00025%, 4/1600906 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.34055e-05; MAF= 0.00134%, 1/74596 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.140
- BayesDel
- -0.456
How the predictions were used
BP4 SupportingMultiple lines of computational evidence predict no impact on the gene product. REVEL score is 0.14 (benign-leaning), BayesDel score is −0.455671 (predicted benign), and SpliceAI predicts no splice alteration (max delta = 0.01). Additionally, the amino acid substitution is conservative (Asp→Glu; both are acidic residues with similar biochemical properties), further supporting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.14 (low
- benign range)
- BayesDel: −0.455671 (predicted benign)
- SpliceAI max delta: 0.01 (no splice impact)
- Conservative substitution: Asp2203→Glu (both acidic
- similar size)
Sources
PP3 Multiple in silico prediction tools uniformly predict a benign effect. REVEL score is 0.14 (well below 0.5 threshold), BayesDel score is −0.455671 (negative = predicted benign), and SpliceAI delta score is 0.01 (no predicted splice impact). No computational tool supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.14 (benign-leaning)
- BayesDel: −0.455671 (predicted benign)
- SpliceAI max delta: 0.01 (no splice impact)
Sources
BP7 N/ANM_002944.2:c.6609C>A is a missense variant (p.Asp2203Glu), not a synonymous variant. BP7 (synonymous variant with no predicted splice impact) does not apply. Details ▾Hide ▴
Evidence considered
- Variant class: missense
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.14. BayesDel score = -0.455671.
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
4 / 1,600,906 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
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.6609C%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/6-117622261-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr6-117301098-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/6-117301098-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002944.2%3Ac.6609…
- OncoKB ↗www.oncokb.org/gene/ROS1/D2203E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ROS1+c.6609C%3EA
- 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
This variant is present in gnomAD v4.1 (AF= 2.49859e-06; MAF= 0.00025%, 4/1600906 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.34055e-05; MAF= 0.00134%, 1/74596 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
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 = 0.01). REVEL score = 0.14. BayesDel score = -0.455671.
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.