NM_002944.2:c.6497C>G

ROS1 · NP_002935.2:p.(Ser2166Cys) · NM_002944.2

GRCh37: chr6:117630029 G>C · GRCh38: chr6:117308866 G>C

Gene: ROS1 Transcript: NM_002944.2

Final call

VUS

PM2 supporting

Variant details

Gene

ROS1

Transcript

NM_002944.2

Protein

NP_002935.2:p.(Ser2166Cys)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This 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).	pvs1_variant_assessment pvs1_gene_context
PS1	Not met	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.	clinvar pm5_candidates
PS2	Not met	No de novo observations have been reported for this variant in any proband. No pedigree or parentage data are available.
PS3	Not met	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.	oncokb
PS4	Not met	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.	clinvar
PS5	N/A	PS5 is not a recognized criterion in the generic ACMG/AMP 2015 classification framework (Richards et al., PMID:25741868).	generic_acmg_combination_rules
PM1	Not met	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.	oncokb
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 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.
PM4	N/A	PM4 applies to protein-length changing variants (non-frameshift deletions/insertions, stop-loss); this is a missense substitution.
PM5	Not met	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.	pm5_candidates clinvar
PM6	Not met	No de novo observations have been reported for this variant. PM6 requires confirmed de novo occurrence with maternity and paternity confirmed.
PP1	Not met	No co-segregation data are available. No family studies or pedigrees include this variant.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	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.
PP5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	This variant is absent from gnomAD. The BA1 threshold of >1% population allele frequency is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD. The BS1 threshold of >0.3% population allele frequency is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observations exist in healthy adult control populations to suggest this is a benign polymorphism. The variant is absent from gnomAD.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies have been performed on this variant to demonstrate a neutral or benign effect. OncoKB provides no benign functional data.	oncokb
BS4	Not met	No segregation data are available to demonstrate lack of co-segregation with disease. No family studies include this variant.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	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.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a substitution variant.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	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.
BP6	Not met	No reputable source has classified this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a missense variant (p.Ser2166Cys).

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