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ROS1c.6100C>TUncertain significance
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Variant interpretation report

ROS1 c.6100C>T, p.(Leu2034Phe)

NM_002944.2:c.6100C>T NP_002935.2:p.(Leu2034Phe) 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: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

Variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant (allele frequency <0.1% in all populations).

PP3Supporting
PP3 · supporting

REVEL score of 0.918 predicts a deleterious effect (threshold >0.75). BayesDel score of 0.34143 also exceeds the pathogenicity threshold (>0.27). Multiple lines of computational evidence support a deleterious effect on the protein.

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, PP3 supporting; combination = 2 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
0.100 maximum delta

Recorded SpliceAI maximum delta score: 0.100. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → 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
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: 2 met · 22 not met · 0 not assessed · 2 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.6100C>T (p.Leu2034Phe) is a missense variant in exon 38 of ROS1, encoding a residue within the kinase domain of this receptor tyrosine kinase.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting PM2 at supporting strength.

REVEL score of 0.918 predicts a deleterious effect, and BayesDel score of 0.34143 exceeds the threshold for pathogenicity, meeting PP3 at supporting strength.

The variant is absent from ClinVar and has not been reported in the published literature. No functional studies, de novo reports, cosegregation data, or case-control analyses are available.

With only two supporting criteria (PM2_Supporting + PP3_Supporting), the evidence is insufficient for classification as likely pathogenic or likely benign under the ACMG/AMP 2015 framework. This variant is classified as a Variant of Uncertain Significance (VUS).

Met · 2

PM2 SupportingVariant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, consistent with a rare variant (allele frequency <0.1% in all populations). Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
  • Absent from gnomAD-Canada v1.0 (genomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL score of 0.918 predicts a deleterious effect (threshold >0.75). BayesDel score of 0.34143 also exceeds the pathogenicity threshold (>0.27). Multiple lines of computational evidence support a deleterious effect on the protein. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.918 (deleterious).
  • BayesDel: 0.34143 (deleterious).
Sources
revelbayesdel

Not met · 22 · evaluated, threshold not reached

PS1 No previously established pathogenic variant with the same amino acid change (p.Leu2034Phe) at this codon has been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic Leu2034Phe comparator identified.
Sources
clinvar ↗
PS2 No de novo occurrence data with confirmed maternity and paternity available for this variant in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No de novo reports found in ClinVar or literature.
Sources
clinvar ↗
PS3 No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect for ROS1 L2034F. No publications with functional characterization of this variant were found. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect
  • no functional data in literature.
Still missing
  • No experimental functional characterization of p.Leu2034Phe available.
Sources
oncokb ↗
PS4 No case-control studies or statistical enrichment data available. Variant is absent from gnomAD, precluding odds ratio calculation. Details ▾Hide ▴
Evidence considered
  • Variant absent from all population databases
  • no case-control enrichment data.
Still missing
  • No case-control enrichment analysis available.
Sources
gnomad_v2 ↗gnomad_v4 ↗
PM1 This variant does not lie in a statistically significant hotspot per cancerhotspots.org. While position 2034 falls within the kinase domain of ROS1, no variant-specific domain-level functional characterization or established mutational hotspot has been demonstrated at this residue. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org: residue not significant
  • no domain-level hotspot established for this position.
Still missing
  • Kinase domain context not fully characterized for this residue.
PM5 No pathogenic missense variants at the same amino acid residue (Leu2034) identified in ClinVar. PM5 candidate harvesting returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates
  • 0 expert panel PLP candidates.
Sources
pm5_candidates
PM6 No de novo occurrence data (without confirmed maternity and paternity) available in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified
  • variant absent from ClinVar.
Sources
clinvar ↗
PP1 No cosegregation data with disease in multiple affected family members available. Details ▾Hide ▴
Evidence considered
  • No family/pedigree or cosegregation data.
Still missing
  • No family history or pedigree information provided.
PP2 HCI prior not available for ROS1. While ROS1 is a receptor tyrosine kinase with described germline variants, no gene-level missense constraint metrics (e.g., Z-score) are available to demonstrate a low rate of benign missense variation. Details ▾Hide ▴
Evidence considered
  • HCI prior: gene not supported
  • no missense constraint data available.
Still missing
  • No missense constraint metrics (Z-score) available for ROS1.
PP4 No patient phenotype or family history information is available to assess specificity for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
  • No phenotype data provided.
Still missing
  • No clinical phenotype information available.
PP5 Variant is absent from ClinVar; no reputable source has reported this variant as pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar: no submissions.
  • OncoKB: Unknown Oncogenic Effect.
Sources
clinvar ↗oncokb ↗
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is well below the 1% BA1 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0.0 (absent) in all gnomAD databases.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Variant is absent from gnomAD. Allele frequency is well below the >0.3% BS1 threshold for non-VCEP assessment. Details ▾Hide ▴
Evidence considered
  • Allele frequency: 0.0 (absent) in all gnomAD databases.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data on healthy adult carriers. Variant is absent from all population databases. Details ▾Hide ▴
Evidence considered
  • No healthy adult observations identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this variant. Details ▾Hide ▴
Evidence considered
  • No functional studies showing benign effect identified.
Still missing
  • No experimental functional data available for p.Leu2034Phe.
Sources
oncokb ↗
BS4 No segregation data in affected family members available; no evidence of lack of segregation. Details ▾Hide ▴
Evidence considered
  • No family/segregation data available.
Still missing
  • No pedigree or segregation information.
BP1 Insufficient evidence to determine that only truncating variants cause ROS1-related disease. Published literature reports both truncating and missense variants in ROS1 (PMID:32906649). BP1 cannot be applied. Details ▾Hide ▴
Evidence considered
  • Missense and splice variants reported in ROS1 germline disease context (PMID:32906649)
  • missense is not excluded as a disease mechanism.
BP2 No data on observations in trans with a pathogenic variant or in cis with a pathogenic variant. Details ▾Hide ▴
Evidence considered
  • No in trans or in cis data available.
BP4 REVEL score of 0.918 predicts a deleterious effect, and BayesDel (0.34143) also exceeds the pathogenicity threshold. Computational evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.918 (deleterious
  • contradicts BP4).
  • BayesDel: 0.34143 (not supporting benign impact).
Sources
revelbayesdel
BP5 No alternate molecular basis for disease has been identified in cases harboring this variant. Details ▾Hide ▴
Evidence considered
  • No alternate molecular diagnosis data available.
BP6 Variant is absent from ClinVar; no reputable source has reported this variant as benign. Details ▾Hide ▴
Evidence considered
  • ClinVar: no submissions
  • no benign reports from any source.
Sources
clinvar ↗
PS5 No established pathogenic missense variant at codon 2034 identified in ClinVar. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • No pathogenic variant at codon 2034 in ClinVar.
Sources
clinvar ↗
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (c.6100C>T, p.Leu2034Phe) does not meet PVS1 null variant criteria per ClinGen SVI PVS1 recommendations (PMC6185798). PVS1 is restricted to nonsense, frameshift, canonical ±1/2 splice consensus, initiation codon, and exon deletion variants. Details ▾Hide ▴
Evidence considered
  • Variant class: substitution
  • variant bucket: other
  • not a null variant type.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/AVariant is a missense change (c.6100C>T, p.Leu2034Phe), not a synonymous (silent) variant. BP7 is restricted to synonymous variants with no predicted splice impact and low nucleotide conservation. Details ▾Hide ▴
Evidence considered
  • Variant class: substitution (missense). BP7 applies only to synonymous variants.

Identifiers

Gene
ROS1
Transcript
NM_002944.2
Coding (HGVS c.)
NM_002944.2:c.6100C>T
Protein (HGVS p.)
NP_002935.2:p.(Leu2034Phe)
GRCh38
chr6:117317178 G>A
GRCh37
chr6:117638341 G>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…
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 +94 bp
0.100
SpliceAI acceptor gainat +2 bp
0.000
SpliceAI donor lossat -35 bp
0.100
SpliceAI donor gainat +94 bp
0.000
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.000

Other predictors

REVEL
0.918
BayesDel
0.341

How the predictions were used

PP3 SupportingREVEL score of 0.918 predicts a deleterious effect (threshold >0.75). BayesDel score of 0.34143 also exceeds the pathogenicity threshold (>0.27). Multiple lines of computational evidence support a deleterious effect on the protein. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.918 (deleterious).
  • BayesDel: 0.34143 (deleterious).
Sources
revelbayesdel
BP4 REVEL score of 0.918 predicts a deleterious effect, and BayesDel (0.34143) also exceeds the pathogenicity threshold. Computational evidence does not support a benign interpretation. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.918 (deleterious
  • contradicts BP4).
  • BayesDel: 0.34143 (not supporting benign impact).
Sources
revelbayesdel
BP7 N/AVariant is a missense change (c.6100C>T, p.Leu2034Phe), not a synonymous (silent) variant. BP7 is restricted to synonymous variants with no predicted splice impact and low nucleotide conservation. Details ▾Hide ▴
Evidence considered
  • Variant class: substitution (missense). BP7 applies only to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). REVEL score = 0.918. BayesDel score = 0.34143.

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 0.100 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 = 0.10). REVEL score = 0.918. BayesDel score = 0.34143.

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.