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.1 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.2 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 BP4.3 With only PM2 (supporting) met, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework.4
ROS1
Final classification
VUS
ROS1 c.5977G>A · p.Glu1993Lys
ROS1
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.
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 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
ROS1 c.5977G>A
PM2
→
VUS
3
revelbayesdelspliceai ↗
4
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 · 20 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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).
Absent from gnomAD v2.1. gnomAD v4.1: AF=6.2e-7 (1/1612930 alleles). Absent from gnomAD-Canada. All frequencies well below 0.1% PM2 threshold.
Assessed · not applied
Pathogenic
PS1
No known pathogenic variant with the same amino acid change (p.Glu1993Lys) has been identified in ClinVar or the literature.
PS2
No evidence of de novo occurrence has been reported for this variant.
PS3
No variant-specific functional studies or systematic-range characterization encompassing position p.Glu1993 have been identified.
PS4
No case-control association studies or statistical evidence of enrichment in affected individuals have been identified for this variant.
PM1
Position p.Glu1993 lies in the C-terminal tail of the ROS1 receptor tyrosine kinase, beyond the catalytic kinase domain.
PM5
No pathogenic missense variants at the same amino acid residue (p.Glu1993) have been identified in ClinVar to serve as PM5 comparators.
PM6
No de novo occurrence has been reported for this variant.
PP1
No segregation data are available for this variant.
PP2
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.
PP3
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).
PP4
No clinical phenotype or family history data are available for this case to evaluate phenotypic specificity.
Benign
BA1
Global allele frequency of 6.2e-7 (0.000062%) in gnomAD v4.1 is well below the 1% threshold required for BA1.
BS1
Global allele frequency of 6.2e-7 (0.000062%) in gnomAD v4.1 is well below the 0.3% threshold required for BS1.
BS2
The single gnomAD v4.1 observation (1/1,612,930 alleles) does not constitute observation at significant frequency in healthy adults.
BS3
No functional studies demonstrating a lack of deleterious effect are available for this variant.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
BP1
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
No evidence of this variant observed in trans with a known pathogenic ROS1 variant.
BP4
REVEL score of 0.739 is above the deleterious threshold, predicting a damaging effect.
BP5
No evidence of an alternative molecular basis for disease has been identified in an individual carrying this variant.
N/A · 4
PVS1 · PP5 · BP6 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 6.1999e-07; MAF= 0.00006%, 1/1612930 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47962e-07; MAF= 0.00008%, 1/1179298 alleles, homozygotes = 0).
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
6.2e-05%
· 1 / 1,612,930
0 hom
0 hom
European (non-Finnish) 1 / 1,179,298 |
8.5e-05% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
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 = 0.06). REVEL score = 0.739. BayesDel score = 0.237318.
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 previously been reported in somatic cancers (COSMIC; COSV107471481, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links