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ROS1c.5977G>AUncertain significance
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Variant interpretation report

ROS1 c.5977G>A, p.(Glu1993Lys)

NM_002944.2:c.5977G>A NP_002935.2:p.(Glu1993Lys) View identifiers
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.

About ROS1

No gene-level summary was recorded for this case.

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
PM2Supporting
PM2 · supporting

This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada. In gnomAD v4.1, the global allele frequency is 6.2e-7 (1/1,612,930 alleles; 0.000062%), well below the 0.1% threshold for PM2. The highest subpopulation frequency is in European (non-Finnish) at 8.48e-7 (1/1,179,298 alleles).

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 supporting; combination = 1 supporting, 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.

SpliceAI score
0.060 maximum delta

Recorded SpliceAI maximum delta score: 0.060. 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
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV107471481, n = 1 times).

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.

26 criteria with recorded statuses: 1 met · 20 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002944.2:c.5977G>A (p.Glu1993Lys) is a missense variant in ROS1, a receptor tyrosine kinase with germline disease associations in familial lung cancer and hereditary breast cancer.

This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at a global frequency of 6.2e-7 (1/1,612,930 alleles), meeting PM2 at supporting strength.

The variant is absent from ClinVar and has not been reported in the literature with variant-specific evidence. No functional studies, segregation data, or case-control associations are available.

In silico predictions are discordant: REVEL (0.739) predicts a deleterious effect while BayesDel (0.237) and SpliceAI (max delta 0.06) do not, failing to meet criteria for PP3 or BP4.

With only PM2 (supporting) met, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework.

Met · 1

PM2 SupportingThis variant is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada. In gnomAD v4.1, the global allele frequency is 6.2e-7 (1/1,612,930 alleles; 0.000062%), well below the 0.1% threshold for PM2. The highest subpopulation frequency is in European (non-Finnish) at 8.48e-7 (1/1,179,298 alleles). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1. gnomAD v4.1: AF=6.2e-7 (1/1
  • 612
  • 930 alleles). Absent from gnomAD-Canada. All frequencies well below 0.1% PM2 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 20 · evaluated, threshold not reached

PS1 No known pathogenic variant with the same amino acid change (p.Glu1993Lys) has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no same-amino-acid pathogenic comparator identified.
Sources
clinvar ↗
PS2 No evidence of de novo occurrence has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified in ClinVar or the literature.
Still missing
  • Absence of parental testing data.
PS3 No variant-specific functional studies or systematic-range characterization encompassing position p.Glu1993 have been identified. OncoKB assigns Unknown Oncogenic Effect with no supporting literature. The single COSMIC somatic observation (COSV107471481) provides no functional characterization. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no supporting PMIDs. COSMIC: one somatic occurrence
  • no functional data.
Still missing
  • No experimental functional data for this variant or for a systematically characterized range that includes p.Glu1993.
Sources
oncokb ↗
PS4 No case-control association studies or statistical evidence of enrichment in affected individuals have been identified for this variant. Details ▾Hide ▴
Evidence considered
  • No case-control or association data available.
Still missing
  • No case-control studies involving ROS1 p.Glu1993Lys.
PM1 Position p.Glu1993 lies in the C-terminal tail of the ROS1 receptor tyrosine kinase, beyond the catalytic kinase domain. This residue is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no published functional domain characterization was identified that specifically defines this C-terminal region as a critical domain where missense variants are established as pathogenic. Details ▾Hide ▴
Evidence considered
  • Not in a cancerhotspots.org hotspot
  • no evidence of a well-characterized critical functional domain at this C-terminal residue.
Still missing
  • Lack of domain-level functional characterization for the C-terminal region of ROS1.
PM5 No pathogenic missense variants at the same amino acid residue (p.Glu1993) have been identified in ClinVar to serve as PM5 comparators. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned no same-residue pathogenic comparators at p.Glu1993 in ClinVar.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence has been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • Absence of parental testing data.
PP1 No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No family segregation information available.
Still missing
  • No family studies or segregation analysis.
PP2 No gene-level constraint metrics (missense Z-score or o/e ratio) were available to determine whether ROS1 has a low rate of benign missense variation. Without such data, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • No gnomAD gene constraint data (missense Z-score
  • o/e) available for ROS1 in this assessment.
Still missing
  • Gene-level missense constraint metrics not available.
PP3 REVEL score of 0.739 exceeds the deleterious threshold (>0.7), but BayesDel score of 0.237 is below the damaging threshold, and SpliceAI predicts no splicing impact (max delta score 0.06). Only one of three computational predictors supports a deleterious effect; multiple lines of computational evidence are required for PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.739 (damaging). BayesDel: 0.237 (below threshold). SpliceAI max delta: 0.06 (no impact). Insufficient multiple lines of concordant in silico evidence.
Sources
revelbayesdelspliceai ↗
PP4 No clinical phenotype or family history data are available for this case to evaluate phenotypic specificity. Details ▾Hide ▴
Evidence considered
  • No clinical phenotype or family history data provided.
Still missing
  • No clinical phenotype information available.
BA1 Global allele frequency of 6.2e-7 (0.000062%) in gnomAD v4.1 is well below the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=6.2e-7
  • far below the 1% BA1 threshold. Absent from gnomAD v2.1 and gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 Global allele frequency of 6.2e-7 (0.000062%) in gnomAD v4.1 is well below the 0.3% threshold required for BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=6.2e-7
  • far below the 0.3% BS1 threshold. Absent from gnomAD v2.1 and gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 The single gnomAD v4.1 observation (1/1,612,930 alleles) does not constitute observation at significant frequency in healthy adults. No evidence this variant has been observed in multiple healthy individuals. Details ▾Hide ▴
Evidence considered
  • Single heterozygous observation in gnomAD v4.1 does not meet BS2 threshold.
Sources
gnomad_v4 ↗
BS3 No functional studies demonstrating a lack of deleterious effect are available for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies identified for this variant.
Still missing
  • No experimental data demonstrating benign functional impact.
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴
Evidence considered
  • No family segregation data available.
Still missing
  • No segregation analysis data.
BP1 Germline missense variants in ROS1 have been reported in disease contexts including familial lung cancer (PMID:41390056) and hereditary breast cancer (PMID:32906649), indicating that pathogenicity in ROS1 is not limited to truncating variants. Details ▾Hide ▴
Evidence considered
  • Published germline disease associations for ROS1 include missense variants
  • not only truncating variants.
BP2 No evidence of this variant observed in trans with a known pathogenic ROS1 variant. Details ▾Hide ▴
Evidence considered
  • No reports of this variant in trans with a pathogenic ROS1 variant.
BP4 REVEL score of 0.739 is above the deleterious threshold, predicting a damaging effect. BayesDel (0.237) and SpliceAI (max delta 0.06) are non-supportive, but multiple lines of computational evidence do not suggest a benign impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.739 (deleterious prediction). Computational evidence does not support a benign interpretation.
Sources
revelbayesdelspliceai ↗
BP5 No evidence of an alternative molecular basis for disease has been identified in an individual carrying this variant. Details ▾Hide ▴
Evidence considered
  • No case data available with an alternative molecular diagnosis.
Still missing
  • No clinical case data available.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense substitution (p.Glu1993Lys) that does not fall into the null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 application per the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution in exon 37
  • not predicted to cause loss of function via null-variant mechanism.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PP5 N/APP5 is not a standard criterion in the ACMG/AMP 2015 classification framework and no gene-specific VCEP/CSPEC framework is available for ROS1. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ABP6 is not a standard criterion in the ACMG/AMP 2015 classification framework and no gene-specific VCEP/CSPEC framework is available for ROS1. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant resulting in an amino acid change (p.Glu1993Lys). BP7 applies only to synonymous/silent variants or variants predicted to have no impact on splicing. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 is not a standard criterion in the ACMG/AMP 2015 classification framework and no gene-specific VCEP/CSPEC framework is available for ROS1. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
ROS1
Transcript
NM_002944.2
Coding (HGVS c.)
NM_002944.2:c.5977G>A
Protein (HGVS p.)
NP_002935.2:p.(Glu1993Lys)
GRCh38
chr6:117318216 C>T
GRCh37
chr6:117639379 C>T
COSMIC
COSV107471481

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…
gnomAD v4.1 1 / 1,612,930 alleles AF 6.2e-07 · 0 homozygotes
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.2e-07 · 1 / 1,612,930 alleles · 0 hom
European (non-Finnish)1 / 1,179,298 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.1999e-07; MAF= 0.00006%, 1/1612930 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47962e-07; MAF= 0.00008%, 1/1179298 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +36 bp
0.040
SpliceAI acceptor gainat +27 bp
0.000
SpliceAI donor lossat -28 bp
0.060
SpliceAI donor gainat -232 bp
0.000
Pangolin splice lossmagnitude shown
-0.070
Pangolin splice gain
0.020

Other predictors

REVEL
0.739
BayesDel
0.237

How the predictions were used

PP3 REVEL score of 0.739 exceeds the deleterious threshold (>0.7), but BayesDel score of 0.237 is below the damaging threshold, and SpliceAI predicts no splicing impact (max delta score 0.06). Only one of three computational predictors supports a deleterious effect; multiple lines of computational evidence are required for PP3. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.739 (damaging). BayesDel: 0.237 (below threshold). SpliceAI max delta: 0.06 (no impact). Insufficient multiple lines of concordant in silico evidence.
Sources
revelbayesdelspliceai ↗
BP4 REVEL score of 0.739 is above the deleterious threshold, predicting a damaging effect. BayesDel (0.237) and SpliceAI (max delta 0.06) are non-supportive, but multiple lines of computational evidence do not suggest a benign impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.739 (deleterious prediction). Computational evidence does not support a benign interpretation.
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant resulting in an amino acid change (p.Glu1993Lys). BP7 applies only to synonymous/silent variants or variants predicted to have no impact on splicing. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.06). REVEL score = 0.739. BayesDel score = 0.237318.

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 1 / 1,612,930 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.060 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

This variant is present in gnomAD v4.1 (AF= 6.1999e-07; MAF= 0.00006%, 1/1612930 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47962e-07; MAF= 0.00008%, 1/1179298 alleles, homozygotes = 0).

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 = 0.06). REVEL score = 0.739. BayesDel score = 0.237318.

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 previously been reported in somatic cancers (COSMIC; COSV107471481, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.