Classification rationale

PM2 VUS

ROS1 c.6497C>G

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.¹ 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.² 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).³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗clinvar ↗

3 generic_acmg_combination_rules

Gene diagram · NM_002944.2 · variants mapped to exon structure

ROS1 NM_002944.2

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 22 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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.

Absent from gnomAD v2.1 (0 alleles)absent from gnomAD v4.1 (0 alleles)absent from gnomAD-Canada v1.0 (0 alleles).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No alternative nucleotide change at c.6497 resulting in the same p.Ser2166Cys amino acid change has been established as pathogenic.

PS2 No de novo observations have been reported for this variant in any proband.

PS3 No variant-specific functional studies exist for p.Ser2166Cys.

PS4 This variant is absent from ClinVar and COSMIC.

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.

PM5 No pathogenic missense variant at the same amino acid residue (Ser2166) has been identified in ClinVar or the literature.

PM6 No de novo observations have been reported for this variant.

PP1 No co-segregation data are 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.

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).

PP4 No clinical phenotype or family history data are associated with this variant.

PP5 No reputable source has classified this variant as pathogenic.

Benign

BA1 This variant is absent from gnomAD.

BS1 This variant is absent from gnomAD.

BS2 No observations exist in healthy adult control populations to suggest this is a benign polymorphism.

BS3 No functional studies have been performed on this variant to demonstrate a neutral or benign effect.

BS4 No segregation data are available to demonstrate lack of co-segregation with disease.

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).

BP2 No data available regarding observation in trans with a pathogenic variant in a gene associated with a recessive disorder.

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.

BP5 No data are available to indicate this variant was found in a case with an alternative molecular basis for disease.

BP6 No reputable source has classified this variant as benign.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

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.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots