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ROS1c.6079G>AUncertain significance
Print report
Variant interpretation report

ROS1 c.6079G>A, p.(Glu2027Lys)

NM_002944.2:c.6079G>A NP_002935.2:p.(Glu2027Lys) 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

NM_002944.2:c.6079G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant not observed in large population cohorts. Under generic ACMG/AMP rules, absence from population databases supports PM2 at supporting level.

PP3Supporting
PP3 · supporting

REVEL predicts a damaging score of 0.923 for NM_002944.2:c.6079G>A (p.Glu2027Lys), well above the 0.75 threshold for pathogenic prediction. BayesDel score of 0.4228 provides moderate additional support. SpliceAI predicts no splice impact (max delta 0.15). The preponderance of in silico evidence supports a deleterious effect.

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
0.150 maximum delta

Recorded SpliceAI maximum delta score: 0.150. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions

1 Uncertain significance.

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; COSV107471754, 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.

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
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002944.2:c.6079G>A (p.Glu2027Lys) is a rare missense variant in the ROS1 gene, absent from all gnomAD population databases (v2.1, v4.1, gnomAD-Canada).

In silico analysis predicts a deleterious effect: REVEL score 0.923 (strongly pathogenic), BayesDel score 0.4228 (moderately pathogenic). SpliceAI predicts no splice impact (max delta 0.15).

This variant has been reported once in COSMIC (COSV107471754) as a somatic alteration and is classified as Uncertain Significance in ClinVar (VariationID 2443073, 1 submitter, no assertion criteria provided).

No variant-specific functional studies, case-control data, segregation data, or de novo observations were identified. OncoKB reports Unknown Oncogenic Effect.

Under generic ACMG/AMP 2015 criteria, this variant meets PM2 (supporting: absent from population databases) and PP3 (supporting: in silico prediction of deleterious effect). All other assessed criteria are not met or not applicable.

With two supporting-level pathogenic criteria (PM2_supporting + PP3_supporting) and no benign criteria met, the evidence is insufficient to classify this variant as likely pathogenic. The variant remains a Variant of Uncertain Significance per ACMG/AMP 2015 classification rules (PMID:25741868).

Met · 2

PM2 SupportingNM_002944.2:c.6079G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant not observed in large population cohorts. Under generic ACMG/AMP rules, absence from population databases supports PM2 at supporting level. 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 predicts a damaging score of 0.923 for NM_002944.2:c.6079G>A (p.Glu2027Lys), well above the 0.75 threshold for pathogenic prediction. BayesDel score of 0.4228 provides moderate additional support. SpliceAI predicts no splice impact (max delta 0.15). The preponderance of in silico evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.923 (strongly pathogenic prediction).
  • BayesDel: 0.4228 (moderate pathogenic prediction).
  • SpliceAI: max delta 0.15 (no splice impact
  • splice prediction is neutral
  • not contradictory).
Sources
revelbayesdelspliceai ↗

Not met · 18 · evaluated, threshold not reached

PS2 No de novo observation has been reported for NM_002944.2:c.6079G>A. No parental testing data are available. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in any evidence source.
Still missing
  • No trio or parental testing data available.
PS3 No variant-specific functional studies were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence. No publications with functional data for p.Glu2027Lys were found. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies found.
Still missing
  • No functional assay data for p.Glu2027Lys.
Sources
oncokb ↗
PS4 No case-control studies demonstrating enrichment of NM_002944.2:c.6079G>A in affected individuals versus controls are available. The variant is absent from gnomAD, precluding statistical comparison. Details ▾Hide ▴
Evidence considered
  • No case-control or enrichment data available.
Still missing
  • No case-control study data for this variant.
PM1 Position 2027 does not lie within a statistically significant mutational hotspot in ROS1. Cancer Hotspots analysis returned no significant enrichment at this residue. Details ▾Hide ▴
Evidence considered
  • Cancer Hotspots: residue 2027 not a significant hotspot.
PM6 No de novo observation has been reported for NM_002944.2:c.6079G>A. PM6 requires a confirmed de novo event, which is not available. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • No trio or de novo testing data.
PP1 No co-segregation data are available for NM_002944.2:c.6079G>A. No family studies reporting segregation of this variant with disease have been identified. Details ▾Hide ▴
Evidence considered
  • No co-segregation data available.
Still missing
  • No family segregation studies.
PP2 Missense constraint data for ROS1 are not available (HCI prior lookup returned 'gene_not_supported'). Without evidence that ROS1 has a low rate of benign missense variation, PP2 cannot be applied. Details ▾Hide ▴
Evidence considered
  • HCI Prior: gene not supported
  • no missense constraint data available for ROS1.
Still missing
  • No missense constraint metric (Z-score
  • HCI prior) available for ROS1.
PP4 No patient phenotype data are available for this adjudication. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease. Without clinical context, this criterion cannot be assessed. Details ▾Hide ▴
Evidence considered
  • No patient phenotype or clinical information provided.
Still missing
  • Patient phenotype and family history not available for review.
BA1 NM_002944.2:c.6079G>A is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires allele frequency >1%, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
  • frequency is 0%
  • far below the 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_002944.2:c.6079G>A is absent from gnomAD. BS1 requires allele frequency >0.3%, which is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD populations
  • frequency is 0%
  • far below the 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No data are available on observation of NM_002944.2:c.6079G>A in healthy adult individuals. The variant is absent from gnomAD, precluding assessment of its presence in presumed healthy controls. Details ▾Hide ▴
Evidence considered
  • No evidence of the variant in healthy individuals
  • absent from population databases.
Still missing
  • No data on variant presence in confirmed healthy controls.
BS3 No functional studies demonstrating a neutral or benign effect of p.Glu2027Lys have been identified. OncoKB reports Unknown Oncogenic Effect with no benign functional evidence. Details ▾Hide ▴
Evidence considered
  • No functional assay showing no damaging effect for p.Glu2027Lys.
Still missing
  • No benign functional evidence available.
Sources
oncokb ↗
BS4 No segregation data are available to demonstrate lack of co-segregation with disease. BS4 requires evidence that the variant does not segregate with the phenotype. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family segregation studies to assess co-segregation or lack thereof.
BP1 Although ROS1 loss of function is supported as a disease mechanism per the PVS1 gene context literature review, the evidence does not establish that only truncating variants cause disease. Published germline studies of ROS1 report both missense and splice site variants in affected individuals (PMID:32906649). BP1 requires that primarily truncating variants are known to cause disease, which is not clearly established for ROS1. Details ▾Hide ▴
Evidence considered
  • ROS1 germline literature describes both missense and truncating variants
  • primarily truncating mechanism not established.
Still missing
  • No definitive evidence that ROS1 disease is exclusively or primarily caused by truncating variants.
BP2 No evidence that NM_002944.2:c.6079G>A has been observed in trans with a known pathogenic variant in ROS1. BP2 is typically applied in recessive disorders, which are not established for ROS1. Details ▾Hide ▴
Evidence considered
  • No trans configuration data
  • no recessive disease model for ROS1.
BP4 REVEL predicts a damaging score of 0.923, strongly inconsistent with a benign in silico profile. While SpliceAI shows no splice impact (max delta 0.15), the REVEL score alone precludes application of BP4, which requires multiple lines of computational evidence suggesting no impact. The overall in silico profile supports a deleterious effect rather than a benign one. Details ▾Hide ▴
Evidence considered
  • REVEL 0.923 contradicts benign prediction.
  • BayesDel 0.4228 is not strongly benign.
  • SpliceAI 0.15 is neutral for splicing but does not override REVEL.
Sources
revelbayesdelspliceai ↗
BP5 No alternate molecular cause for the observed phenotype has been identified in a case carrying NM_002944.2:c.6079G>A. No case-level data with an alternate molecular diagnosis are available. Details ▾Hide ▴
Evidence considered
  • No case data with an alternate molecular basis for disease.
Still missing
  • No case-level data or alternate molecular diagnosis available.
BP6 ClinVar reports NM_002944.2:c.6079G>A as Uncertain Significance by a single submitter (Salgia Laboratory, City of Hope) with no assertion criteria provided. BP6 requires a reputable source to classify the variant as benign, which is not met. Details ▾Hide ▴
Evidence considered
  • ClinVar: Uncertain significance (1 submitter
  • no assertion criteria). Not classified as benign.
Sources
clinvar ↗
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002944.2:c.6079G>A is a missense substitution (p.Glu2027Lys). PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). This variant does not fall into any PVS1 bucket per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • not a null variant.
Sources
pvs1_generic_framework ↗
PS1 N/ANo pathogenic or likely pathogenic variant with the same amino acid change (p.Glu2027Lys) has been established in ClinVar or the literature. No comparator exists to apply PS1. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no P/LP variant at residue 2027 with a lysine substitution.
Sources
clinvar ↗
PM3 N/APM3 applies to autosomal recessive disorders with a pathogenic variant in trans. No established recessive disease association for ROS1. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to non-repeat in-frame indels or stop-loss variants. This is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANo pathogenic or likely pathogenic missense variant at the same amino acid residue (Glu2027) with a different amino acid change was identified in ClinVar. PM5 candidate harvesting returned zero same-residue comparators. Details ▾Hide ▴
Evidence considered
  • No same-residue P/LP comparator variants found at Glu2027.
Sources
pm5_candidatesclinvar ↗
PP5 N/APP5 is used for autosomal recessive disorders when a pathogenic variant is found in trans. ROS1 is not established as a recessive disease gene. Details ▾Hide ▴
Evidence considered
  • Not applicable
  • no recessive disease model for ROS1.
BP3 N/ABP3 applies to in-frame indels in repetitive regions. This is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002944.2:c.6079G>A is a missense variant (p.Glu2027Lys), not synonymous. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is for synonymous variants only.
PS5 N/APS5 is used for autosomal recessive or X-linked disorders where a pathogenic variant is found in trans. Insufficient data to apply; ROS1-associated phenotypes are not established as recessive. Details ▾Hide ▴
Evidence considered
  • Not applicable
  • no established recessive disease association for ROS1.

Identifiers

Gene
ROS1
Transcript
NM_002944.2
Coding (HGVS c.)
NM_002944.2:c.6079G>A
Protein (HGVS p.)
NP_002935.2:p.(Glu2027Lys)
GRCh38
chr6:117317199 C>T
GRCh37
chr6:117638362 C>T
ClinVar
2443073
COSMIC
COSV107471754

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 +73 bp
0.150
SpliceAI acceptor gainat -56 bp
0.000
SpliceAI donor lossat -56 bp
0.110
SpliceAI donor gainat +73 bp
0.000
Pangolin splice lossmagnitude shown
-0.030
Pangolin splice gain
0.000

Other predictors

REVEL
0.923
BayesDel
0.423

How the predictions were used

PP3 SupportingREVEL predicts a damaging score of 0.923 for NM_002944.2:c.6079G>A (p.Glu2027Lys), well above the 0.75 threshold for pathogenic prediction. BayesDel score of 0.4228 provides moderate additional support. SpliceAI predicts no splice impact (max delta 0.15). The preponderance of in silico evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.923 (strongly pathogenic prediction).
  • BayesDel: 0.4228 (moderate pathogenic prediction).
  • SpliceAI: max delta 0.15 (no splice impact
  • splice prediction is neutral
  • not contradictory).
Sources
revelbayesdelspliceai ↗
BP4 REVEL predicts a damaging score of 0.923, strongly inconsistent with a benign in silico profile. While SpliceAI shows no splice impact (max delta 0.15), the REVEL score alone precludes application of BP4, which requires multiple lines of computational evidence suggesting no impact. The overall in silico profile supports a deleterious effect rather than a benign one. Details ▾Hide ▴
Evidence considered
  • REVEL 0.923 contradicts benign prediction.
  • BayesDel 0.4228 is not strongly benign.
  • SpliceAI 0.15 is neutral for splicing but does not override REVEL.
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_002944.2:c.6079G>A is a missense variant (p.Glu2027Lys), not synonymous. Details ▾Hide ▴
Evidence considered
  • Missense substitution
  • BP7 is for synonymous variants only.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.923. BayesDel score = 0.4228.

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 0.150 Open source ↗
ClinVar 1 Uncertain significance 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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2443073)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.923. BayesDel score = 0.4228.

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; COSV107471754, n = 1 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.