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ROS1c.6497C>GUncertain significance
Print report
Variant interpretation report

ROS1 c.6497C>G, p.(Ser2166Cys)

NM_002944.2:c.6497C>G NP_002935.2:p.(Ser2166Cys) 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 completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 allele frequency threshold of <0.1% for a rare variant absent from population databases.

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
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. 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
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: 1 met · 22 not met · 0 not assessed · 6 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

PM2 is met at supporting strength: the variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, satisfying the population frequency criterion for a rare missense variant.

No other pathogenic or benign criteria are met. In silico predictions are conflicting (REVEL 0.708 vs BayesDel 0.082). No functional, segregation, de novo, or case-control data are available. The variant is absent from ClinVar and COSMIC.

ROS1 has no CSPEC/VCEP expert panel. Generic ACMG/AMP 2015 rules apply. With only one supporting-level pathogenic criterion (PM2) and no benign criteria met, the variant is classified as a Variant of Uncertain Significance (VUS).

Met · 1

PM2 SupportingThis variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 allele frequency threshold of <0.1% for a rare variant absent from population databases. 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
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 22 · evaluated, threshold not reached

PS1 No alternative nucleotide change at c.6497 resulting in the same p.Ser2166Cys amino acid change has been established as pathogenic. No ClinVar entries exist for this residue with any amino acid change. Details ▾Hide ▴
Evidence considered
  • ClinVar contains no entries for position 2166 in ROS1
  • no pathogenic comparator with the same amino acid change identified.
Sources
clinvar ↗pm5_candidates
PS2 No de novo observations have been reported for this variant in any proband. No pedigree or parentage data are available. Details ▾Hide ▴
Evidence considered
  • No publications mention this variant
  • no de novo data exist in ClinVar or any evidence source.
Still missing
  • No trio or de novo testing data available for this variant.
PS3 No variant-specific functional studies exist for p.Ser2166Cys. OncoKB classifies the variant as Unknown Oncogenic Effect. No publications with experimental functional data for this variant were identified. The variant does not fall within a systematically characterized range (tiling screen, saturation mutagenesis, or truncation series) in any study. Details ▾Hide ▴
Evidence considered
  • OncoKB reports Unknown Oncogenic Effect
  • no variant-specific functional data identified in the literature
  • no systematic range characterization includes position 2166.
Still missing
  • No functional assays performed on this variant or on a systematically characterized range that includes position 2166.
Sources
oncokb ↗
PS4 This variant is absent from ClinVar and COSMIC. No proband data, case-control studies, or clinical cohort reports are available to establish statistically significant enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • absent from COSMIC
  • no proband or case-control data available.
Still missing
  • No clinical cohorts or case-control studies report this variant.
Sources
clinvar ↗
PM1 The variant maps to the kinase domain (residues ~1946-2222) but position 2166 is not a statistically significant mutational hotspot (cancerhotspots.org negative) and no functional domain characterization specific to this residue exists. General kinase domain membership alone does not satisfy PM1 without evidence of variant enrichment or residue-level functional criticality. Details ▾Hide ▴
Evidence considered
  • cancerhotspots.org reports no significant hotspot at residue 2166
  • OncoKB gene-level context provides no residue-specific functional data.
Still missing
  • No residue-specific functional characterization of position 2166.
Sources
oncokb ↗
PM5 No pathogenic missense variant at the same amino acid residue (Ser2166) has been identified in ClinVar or the literature. Automated PM5 candidate harvesting was unable to identify any same-residue comparator variants. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search returned 0 same-residue candidates
  • ClinVar has no entries for codon 2166 in ROS1.
Still missing
  • No pathogenic comparator missense variant at codon 2166.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observations have been reported for this variant. PM6 requires confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
  • No publications
  • ClinVar entries
  • or case reports document de novo status.
Still missing
  • No trio or parentage testing data available.
PP1 No co-segregation data are available. No family studies or pedigrees include this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data identified in any source.
Still missing
  • No pedigree or segregation analysis available.
PP2 ROS1 is not established as a gene with a low rate of benign missense variation and where missense variants are a common mechanism of germline disease. The predominant mechanism in cancer involves gene fusions/rearrangements; germline missense constraint has not been characterized. No HCI prior score is available for this gene. Details ▾Hide ▴
Evidence considered
  • No gnomAD missense constraint data (Z-score not available)
  • no HCI prior score available for ROS1
  • gene not in a CSPEC missense-constrained gene list.
Still missing
  • Missense constraint metrics not established for ROS1 in the germline context.
PP3 REVEL score is 0.708 (moderately elevated) but BayesDel score is 0.082 (low, below typical pathogenic thresholds) and SpliceAI predicts no splice impact (max delta 0.01). The in silico predictions are conflicting — only one predictor supports a deleterious effect — and do not constitute multiple lines of computational support for pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.708
  • BayesDel: 0.0819412
  • SpliceAI max delta: 0.01
  • HCI prior: not available.
Still missing
  • Conflicting in silico predictions
  • only REVEL marginally supports pathogenicity.
Sources
revelbayesdelspliceai ↗
PP4 No clinical phenotype or family history data are associated with this variant. No proband with a specific phenotype and relevant family history has been reported. Details ▾Hide ▴
Evidence considered
  • No clinical case reports or phenotype data available.
Still missing
  • No phenotype or family history context available for this variant.
PP5 No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no external laboratory or expert panel classification exists.
Sources
clinvar ↗
BA1 This variant is absent from gnomAD. The BA1 threshold of >1% population allele frequency is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets
  • allele frequency = 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from gnomAD. The BS1 threshold of >0.3% population allele frequency is not met. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets
  • allele frequency = 0%.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No observations exist in healthy adult control populations to suggest this is a benign polymorphism. The variant is absent from gnomAD. Details ▾Hide ▴
Evidence considered
  • Absent from all gnomAD datasets
  • no homozygous or heterozygous observations in controls.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies have been performed on this variant to demonstrate a neutral or benign effect. OncoKB provides no benign functional data. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional data exist
  • OncoKB classifies as Unknown Oncogenic Effect.
Still missing
  • No functional assays demonstrate a benign effect for this variant.
Sources
oncokb ↗
BS4 No segregation data are available to demonstrate lack of co-segregation with disease. No family studies include this variant. Details ▾Hide ▴
Evidence considered
  • No family or segregation studies available.
Still missing
  • No segregation data.
BP1 While ROS1 has evidence of loss-of-function as a disease mechanism, missense variants have also been implicated in germline disease risk (e.g., PMID:32906649 reports damaging missense variants in ROS1 in hereditary breast cancer). BP1 requires that the gene be associated with disease exclusively through truncating variants, which is not established for ROS1. Details ▾Hide ▴
Evidence considered
  • ROS1 germline disease includes both truncating and missense variant mechanisms
  • BP1 does not apply.
Sources
pvs1_gene_context
BP2 No data available regarding observation in trans with a pathogenic variant in a gene associated with a recessive disorder. ROS1 is not established as a recessive disease gene. Details ▾Hide ▴
Evidence considered
  • No trans-configuration data or recessive disease model established for ROS1.
Still missing
  • No data on variant phase or co-occurrence with other variants.
BP4 In silico predictions are conflicting: REVEL (0.708) suggests possible pathogenicity while BayesDel (0.082) suggests benign effect and SpliceAI predicts no splice impact. Multiple lines of computational evidence do NOT concur in suggesting no impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.708 (elevated
  • suggests possible pathogenicity)
  • BayesDel: 0.082 (low
  • benign-like)
  • SpliceAI: 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP5 No data are available to indicate this variant was found in a case with an alternative molecular basis for disease. Without a proband with a definitive alternate diagnosis, BP5 cannot be applied. Details ▾Hide ▴
Evidence considered
  • No clinical case data with alternate molecular diagnosis available.
Still missing
  • No proband data with an alternative molecular diagnosis.
BP6 No reputable source has classified this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
  • Absent from ClinVar
  • no benign classification from any source.
Sources
clinvar ↗
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Ser2166Cys); PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice consensus). The variant does not fall into any PVS1 null-variant bucket per ClinGen SVI recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
  • The variant is a substitution in exon 41 of 43
  • not a null variant type.
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/APM3 applies to variants observed in trans with a pathogenic variant for recessive disorders; no such data are available and ROS1 is not a recessive disease gene. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length changing variants (non-frameshift deletions/insertions, stop-loss); this is a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; this is a substitution variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (p.Ser2166Cys). Details ▾Hide ▴
Evidence considered
  • The variant is missense
  • not synonymous.
PS5 N/APS5 is not a recognized criterion in the generic ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868). Details ▾Hide ▴
Evidence considered
  • PS5 does not appear in the ACMG/AMP 2015 criteria table.
Sources
generic_acmg_combination_rules

Identifiers

Gene
ROS1
Transcript
NM_002944.2
Coding (HGVS c.)
NM_002944.2:c.6497C>G
Protein (HGVS p.)
NP_002935.2:p.(Ser2166Cys)
GRCh38
chr6:117308866 G>C
GRCh37
chr6:117630029 G>C

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 +62 bp
0.010
SpliceAI acceptor gainat +16 bp
0.010
SpliceAI donor lossat -72 bp
0.010
SpliceAI donor gainat -76 bp
0.000
Pangolin splice lossmagnitude shown
-0.040
Pangolin splice gain
0.000

Other predictors

REVEL
0.708
BayesDel
0.082

How the predictions were used

PP3 REVEL score is 0.708 (moderately elevated) but BayesDel score is 0.082 (low, below typical pathogenic thresholds) and SpliceAI predicts no splice impact (max delta 0.01). The in silico predictions are conflicting — only one predictor supports a deleterious effect — and do not constitute multiple lines of computational support for pathogenicity. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.708
  • BayesDel: 0.0819412
  • SpliceAI max delta: 0.01
  • HCI prior: not available.
Still missing
  • Conflicting in silico predictions
  • only REVEL marginally supports pathogenicity.
Sources
revelbayesdelspliceai ↗
BP4 In silico predictions are conflicting: REVEL (0.708) suggests possible pathogenicity while BayesDel (0.082) suggests benign effect and SpliceAI predicts no splice impact. Multiple lines of computational evidence do NOT concur in suggesting no impact. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.708 (elevated
  • suggests possible pathogenicity)
  • BayesDel: 0.082 (low
  • benign-like)
  • SpliceAI: 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (p.Ser2166Cys). Details ▾Hide ▴
Evidence considered
  • The variant is missense
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.708. BayesDel score = 0.0819412.

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 0.010 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

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 = 0.01). REVEL score = 0.708. BayesDel score = 0.0819412.

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.