NM_002944.2:c.5977G>A

ROS1 · NP_002935.2:p.(Glu1993Lys) · NM_002944.2

GRCh37: chr6:117639379 C>T · GRCh38: chr6:117318216 C>T

Gene: ROS1 Transcript: NM_002944.2

Final call

VUS

PM2 supporting

Variant details

Gene

ROS1

Transcript

NM_002944.2

Protein

NP_002935.2:p.(Glu1993Lys)

gnomAD AF

6.199897081708444e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002944.2:c.5977G>A (p.Glu1993Lys) is a missense variant in ROS1, a receptor tyrosine kinase with germline disease associations in familial lung cancer and hereditary breast cancer.

This variant is extremely rare in population databases: absent from gnomAD v2.1 and gnomAD-Canada, and present in gnomAD v4.1 at a global frequency of 6.2e-7 (1/1,612,930 alleles), meeting PM2 at supporting strength.

The variant is absent from ClinVar and has not been reported in the literature with variant-specific evidence. No functional studies, segregation data, or case-control associations are available.

In silico predictions are discordant: REVEL (0.739) predicts a deleterious effect while BayesDel (0.237) and SpliceAI (max delta 0.06) do not, failing to meet criteria for PP3 or BP4.

With only PM2 (supporting) met, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework.

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 substitution (p.Glu1993Lys) that does not fall into the null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 application per the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No known pathogenic variant with the same amino acid change (p.Glu1993Lys) has been identified in ClinVar or the literature.	clinvar
PS2	Not met	No evidence of de novo occurrence has been reported for this variant.
PS3	Not met	No variant-specific functional studies or systematic-range characterization encompassing position p.Glu1993 have been identified. OncoKB assigns Unknown Oncogenic Effect with no supporting literature. The single COSMIC somatic observation (COSV107471481) provides no functional characterization.	oncokb
PS4	Not met	No case-control association studies or statistical evidence of enrichment in affected individuals have been identified for this variant.
PS5	N/A	PS5 is not a standard criterion in the ACMG/AMP 2015 classification framework and no gene-specific VCEP/CSPEC framework is available for ROS1.
PM1	Not met	Position p.Glu1993 lies in the C-terminal tail of the ROS1 receptor tyrosine kinase, beyond the catalytic kinase domain. This residue is not located in a statistically significant mutational hotspot per cancerhotspots.org, and no published functional domain characterization was identified that specifically defines this C-terminal region as a critical domain where missense variants are established as pathogenic.
PM2	Met	This variant is extremely rare in population databases. It is absent from gnomAD v2.1 and gnomAD-Canada. In gnomAD v4.1, the global allele frequency is 6.2e-7 (1/1,612,930 alleles; 0.000062%), well below the 0.1% threshold for PM2. The highest subpopulation frequency is in European (non-Finnish) at 8.48e-7 (1/1,179,298 alleles).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variants at the same amino acid residue (p.Glu1993) have been identified in ClinVar to serve as PM5 comparators.	pm5_candidates clinvar
PM6	Not met	No de novo occurrence has been reported for this variant.
PP1	Not met	No segregation data are available for this variant.
PP2	Not met	No gene-level constraint metrics (missense Z-score or o/e ratio) were available to determine whether ROS1 has a low rate of benign missense variation. Without such data, PP2 cannot be applied.
PP3	Not met	REVEL score of 0.739 exceeds the deleterious threshold (>0.7), but BayesDel score of 0.237 is below the damaging threshold, and SpliceAI predicts no splicing impact (max delta score 0.06). Only one of three computational predictors supports a deleterious effect; multiple lines of computational evidence are required for PP3.	revel bayesdel spliceai
PP4	Not met	No clinical phenotype or family history data are available for this case to evaluate phenotypic specificity.
PP5	N/A	PP5 is not a standard criterion in the ACMG/AMP 2015 classification framework and no gene-specific VCEP/CSPEC framework is available for ROS1.
BA1	Not met	Global allele frequency of 6.2e-7 (0.000062%) in gnomAD v4.1 is well below the 1% threshold required for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Global allele frequency of 6.2e-7 (0.000062%) in gnomAD v4.1 is well below the 0.3% threshold required for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	The single gnomAD v4.1 observation (1/1,612,930 alleles) does not constitute observation at significant frequency in healthy adults. No evidence this variant has been observed in multiple healthy individuals.	gnomad_v4
BS3	Not met	No functional studies demonstrating a lack of deleterious effect are available for this variant.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease.
BP1	Not met	Germline missense variants in ROS1 have been reported in disease contexts including familial lung cancer (PMID:41390056) and hereditary breast cancer (PMID:32906649), indicating that pathogenicity in ROS1 is not limited to truncating variants.
BP2	Not met	No evidence of this variant observed in trans with a known pathogenic ROS1 variant.
BP4	Not met	REVEL score of 0.739 is above the deleterious threshold, predicting a damaging effect. BayesDel (0.237) and SpliceAI (max delta 0.06) are non-supportive, but multiple lines of computational evidence do not suggest a benign impact.	revel bayesdel spliceai
BP5	Not met	No evidence of an alternative molecular basis for disease has been identified in an individual carrying this variant.
BP6	N/A	BP6 is not a standard criterion in the ACMG/AMP 2015 classification framework and no gene-specific VCEP/CSPEC framework is available for ROS1.
BP7	N/A	This is a missense variant resulting in an amino acid change (p.Glu1993Lys). BP7 applies only to synonymous/silent variants or variants predicted to have no impact on splicing.

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