NM_002944.2:c.6565G>T

ROS1 · NP_002935.2:p.(Asp2189Tyr) · NM_002944.2

GRCh37: chr6:117629961 C>A · GRCh38: chr6:117308798 C>A

Gene: ROS1 Transcript: NM_002944.2

Final call

VUS

PM2 moderate

Variant details

Gene

ROS1

Transcript

NM_002944.2

Protein

NP_002935.2:p.(Asp2189Tyr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_002944.2:c.6565G>T (p.Asp2189Tyr) in ROS1 is a missense variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at moderate strength.

This variant does not meet PVS1 criteria as it is a missense substitution, not a null variant eligible under the ClinGen SVI PVS1 decision tree (PMC6185798).

In silico predictions are conflicting: REVEL score of 0.589 is borderline, BayesDel score of -0.169 suggests a benign effect, and SpliceAI predicts no splice impact (max delta 0.02). Neither PP3 nor BP4 is met.

No functional studies, ClinVar classifications, case-control data, segregation data, or literature reports are available for this variant. No criterion beyond PM2 is met.

Overall, the evidence is insufficient for classification. With only PM2 (moderate) met and no other criteria satisfied, this variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 guidelines (PMID:25741868).

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	NM_002944.2:c.6565G>T is a missense variant (p.Asp2189Tyr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework (PMC6185798) applies only to null variants.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No same amino acid change (p.Asp2189Tyr) has been reported as pathogenic in ClinVar or the literature. The variant has no ClinVar entries and no publications describe this amino acid substitution.	clinvar
PS2	Not met	No de novo observation has been reported for this variant in any publication or database.
PS3	Not met	No functional studies have been performed on this variant. OncoKB reports Unknown Oncogenic Effect and no publications with variant-specific functional data were identified.	oncokb
PS4	Not met	No case-control data are available. The variant is absent from ClinVar and no affected individuals have been reported.	clinvar
PS5	Not met	No reputable source has reported this variant as pathogenic. It is absent from ClinVar and OncoKB.	clinvar oncokb
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org. No evidence was identified that residue Asp2189 resides in a critical well-established functional domain without benign variation, based on available case evidence.
PM2	Met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, consistent with rarity in the general population (allele frequency below 0.1% threshold).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No pathogenic missense variant at the same amino acid residue (Asp2189) has been identified. PM5 candidate search found no same-residue comparators in ClinVar.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant.
PP1	Not met	No cosegregation data are available for this variant.
PP2	Not met	HCI Prior data are not available for ROS1 (gene not supported by the predictor). No constraint metrics or missense Z-score are available to assess whether ROS1 has a low rate of benign missense variation.
PP3	Not met	In silico predictions are conflicting: REVEL score of 0.589 is in the borderline range (not clearly pathogenic), BayesDel score of -0.169 suggests a benign effect, and SpliceAI max delta score of 0.02 predicts no splice impact. Multiple lines of computational evidence do not consistently support a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or clinical data were provided for this case. PP4 cannot be assessed without knowing whether the patient's presentation is highly specific for a ROS1-related disorder.
PP5	Not met	No reputable source has reported this variant as pathogenic. It is absent from ClinVar and OncoKB provides no pathogenic classification. ClinVar 3-star expert panel classification is not available.	clinvar oncokb
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency is 0%, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD. Allele frequency is 0%, well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available regarding observation of this variant in healthy adults at an age when full penetrance of a ROS1-related disorder would be expected.
BS3	Not met	No functional studies have been performed on this variant demonstrating a neutral or benign effect.
BS4	Not met	No segregation data are available for this variant.
BP1	Not met	ROS1 encodes a receptor tyrosine kinase. Missense variants in kinase domains are a recognized disease mechanism for receptor tyrosine kinases. BP1 (missense variant in gene where primarily truncating variants cause disease) does not apply.
BP2	Not met	No data are available on observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	In-frame deletion/insertion criterion; variant is a substitution.
BP4	Not met	In silico predictions are conflicting: REVEL 0.589 is borderline (not clearly benign), BayesDel -0.169 suggests a benign effect, and SpliceAI 0.02 shows no splice impact. Multiple lines of computational evidence do not consistently suggest no impact on the gene product.	revel bayesdel spliceai
BP5	Not met	No alternate molecular basis for disease has been identified in a case carrying this variant.
BP6	Not met	No reputable source has reported this variant as benign. It is absent from ClinVar.	clinvar
BP7	N/A	Synonymous variant criterion; NM_002944.2:c.6565G>T is a missense substitution (p.Asp2189Tyr).
PM3	N/A	Requires observation in trans with a pathogenic variant; no such data available for this variant.
PM4	N/A	Protein length change criterion; variant is a missense substitution, not an in-frame deletion/insertion or stop-loss.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.