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.1 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).2 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.3 No functional studies, ClinVar classifications, case-control data, segregation data, or literature reports are available for this variant. No criterion beyond PM2 is met.4 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).5
ROS1
Final classification
VUS
ROS1 c.6565G>T · p.Asp2189Tyr
ROS1
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.
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 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
ROS1 c.6565G>T
PM2
→
VUS
2
pvs1_generic_framework ↗pvs1_variant_assessment
3
revelbayesdelspliceai ↗
5
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
moderate
Pathogenic
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).
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
Assessed · not applied
Pathogenic
PS1
No same amino acid change (p.Asp2189Tyr) has been reported as pathogenic in ClinVar or the literature.
PS2
No de novo observation has been reported for this variant in any publication or database.
PS3
No functional studies have been performed on this variant.
PS4
No case-control data are available.
PM1
This variant does not lie in a statistically significant mutational hotspot per cancerhotspots.org.
PM5
No pathogenic missense variant at the same amino acid residue (Asp2189) has been identified.
PM6
No de novo observation has been reported for this variant.
PP1
No cosegregation data are available for this variant.
PP2
HCI Prior data are not available for ROS1 (gene not supported by the predictor).
PP3
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.
PP4
No patient phenotype or clinical data were provided for this case.
PP5
No reputable source has reported this variant as pathogenic.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from gnomAD.
BS2
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
No functional studies have been performed on this variant demonstrating a neutral or benign effect.
BS4
No segregation data are available for this variant.
BP1
ROS1 encodes a receptor tyrosine kinase.
BP2
No data are available on observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP4
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.
BP5
No alternate molecular basis for disease has been identified in a case carrying this variant.
BP6
No reputable source has reported 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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.589. BayesDel score = -0.169433.
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.
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.
Sources & reference links