Variant classification summary

NM_002944.2:c.5825G>A

ROS1 · NP_002935.2:p.(Arg1942Gln) · NM_002944.2

GRCh37: chr6:117641146 C>T · GRCh38: chr6:117319983 C>T

Gene: ROS1 Transcript: NM_002944.2

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

ROS1

Transcript

NM_002944.2

Protein

NP_002935.2:p.(Arg1942Gln)

gnomAD AF

8.058387355522413e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_002944.2:c.5825G>A (p.Arg1942Gln) is a missense variant in exon 37 of the ROS1 gene, encoding a receptor tyrosine kinase implicated in familial lung cancer and hereditary breast cancer.

2

This variant is present at extremely low frequency in gnomAD v4.1 (AF=0.000081%, 13/1,613,226 alleles, 0 homozygotes) and is absent from gnomAD v2.1. The grpmax filtering allele frequency is 8.75e-06, well below the 0.1% threshold for PM2 at supporting strength.

3

In silico predictors are predominantly deleterious: REVEL score 0.706 (pathogenic-leaning) and SpliceAI max delta 0.99 (predicts acceptor gain with potential splice-altering effect). PP3 is applied at supporting strength.

4

The variant is absent from ClinVar and COSMIC. No variant-specific functional studies, de novo reports, segregation data, or case-control analyses are available in the case materials.

5

PVS1 is not applicable as this is a missense variant. The variant does not lie at a canonical splice consensus position and falls outside the null-variant buckets defined by the ClinGen PVS1 framework (PMC6185798).

6

Only two supporting-level criteria (PM2_Supporting, PP3) are met. Per the ACMG/AMP 2015 combination rules, two supporting criteria are insufficient to reach a Likely Pathogenic classification. The variant is classified as a Variant of Uncertain Significance (VUS).

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.5825G>A is a missense variant (p.Arg1942Gln) and does not fall into the null-variant buckets required for PVS1 (nonsense, frameshift, or canonical ±1,2 splice consensus variants). Although SpliceAI predicts an acceptor gain (delta=0.99), the variant resides at coding position c.5825 in exon 37, 48 bases downstream of the acceptor splice junction, and does not disrupt the canonical splice consensus.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	No ClinVar entry exists for a different nucleotide change resulting in the same amino acid substitution (p.Arg1942Gln). The variant is absent from ClinVar entirely.	clinvar
PS2	Not met	No de novo data are available for NM_002944.2:c.5825G>A. No publications or database records report a de novo observation of this variant.
PS3	Not met	No variant-specific functional data are available for p.Arg1942Gln. OncoKB reports Unknown Oncogenic Effect. No PMIDs with experimental characterization of this variant were identified in the case literature. Domain-level inference from gene function is not sufficient for PS3, which requires direct variant testing or systematic range characterization.	oncokb
PS4	Not met	No case-control or affected-prevalence data are available to demonstrate enrichment of this variant in affected individuals. Population allele counts from gnomAD (13/1,613,226) alone do not satisfy the PS4 requirement for statistically significant enrichment in cases versus controls.
PS5	N/A	No ClinVar pathogenic variant exists at the same amino acid residue (Arg1942) with a different nucleotide change. The variant is absent from ClinVar, and no comparator variants are available for a PS5 assessment.	clinvar
PM1	Not met	p.Arg1942Gln does not lie in a statistically significant mutational hotspot per cancerhotspots.org. No VCEP- or literature-defined critical functional domain encompassing residue 1942 is available in the case materials. While ROS1 contains a tyrosine kinase domain, residue 1942 is positioned just N-terminal to the kinase domain (approx. residues 1945–2215), and no domain-specific functional characterization is provided to satisfy PM1.
PM2	Met	NM_002944.2:c.5825G>A is present at extremely low frequency in gnomAD v4.1 (overall AF=0.000081%, 13/1,613,226 alleles, 0 homozygotes; grpmax FAF=8.75e-06). It is absent from gnomAD v2.1. The allele frequency is well below the 0.1% PM2 threshold for generic ACMG application.	gnomad_v2 gnomad_v4
PM5	N/A	No same-residue ClinVar comparator variants (different amino acid change at Arg1942) were identified. The PM5 candidate harvest produced zero candidates, and no expert-panel pathogenic variants at this position are available.	pm5_candidates
PM6	Not met	No de novo data are available. No publications or database records report a de novo observation of NM_002944.2:c.5825G>A with confirmed maternity and paternity.
PP1	Not met	No segregation data are available for this variant. No family studies or cosegregation analyses were identified in the case materials.
PP2	Not met	Insufficient data to apply PP2. ROS1 lacks a computed missense constraint metric (HCI Prior not available), and the gene does not have an established low rate of benign missense variation. While ROS1 missense variants have been reported in hereditary breast cancer (PMID:32906649), this alone does not satisfy the PP2 requirement for a gene with a low rate of benign missense variation where missense variants are a common disease mechanism.
PP3	Met	Multiple in silico predictors support a deleterious effect. REVEL score 0.706 is above the pathogenic threshold, and SpliceAI predicts a strong cryptic acceptor gain (delta=0.99) that may alter splicing. BayesDel score 0.137 is discordant (benign-leaning). Two independent computational lines (REVEL for missense impact; SpliceAI for splice-altering potential) support a deleterious effect, meeting the PP3 threshold at supporting strength.	revel spliceai bayesdel
PP4	Not met	No patient-specific phenotype or clinical data are available in the case. PP4 requires that the variant is observed in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology, and no such clinical information is provided.
PP5	N/A	NM_002944.2:c.5825G>A is absent from ClinVar. PP5 requires a reputable source (ClinVar 3-star expert panel) to have classified the variant as pathogenic. No ClinVar entry exists for this variant.	clinvar
BA1	Not met	The overall gnomAD v4.1 allele frequency is 0.000081% (8.06e-06), far below the 1% BA1 threshold. The highest subpopulation frequency (East Asian) is 0.00446% (4.46e-05), also well below 1%.	gnomad_v4
BS1	Not met	The overall gnomAD v4.1 allele frequency is 0.000081%, below the 0.3% BS1 threshold. The highest subpopulation frequency (East Asian) is 0.00446%, also well below 0.3%.	gnomad_v4
BS2	Not met	No data on healthy adult carriers are available. BS2 requires observation of the variant in a healthy adult individual for a fully penetrant dominant disorder, and no such data are present in the case materials.
BS3	Not met	No functional studies demonstrating no deleterious effect of p.Arg1942Gln are available. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease are available. BS4 requires observation of the variant in affected family members without disease or inconsistent segregation patterns.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. ROS1 does not meet this requirement: missense variants in ROS1 have been reported in hereditary breast cancer (PMID:32906649), and the gene-level PVS1 context supports both LoF and potential missense disease mechanisms in familial lung cancer (PMID:41390056). The disease mechanism for ROS1 is not exclusively truncating.
BP2	Not met	No data on observation of this variant in trans with a known pathogenic variant are available. BP2 requires the variant to be observed in trans with a pathogenic variant in a recessive disorder, or in cis with a pathogenic variant in a dominant disorder.
BP4	Not met	Computational evidence is not uniformly benign. REVEL 0.706 predicts a damaging effect, and SpliceAI delta 0.99 predicts a splice-altering effect. Only BayesDel (0.137) suggests a benign impact. BP4 requires multiple lines of computational evidence to suggest no impact; the majority of available predictors indicate a deleterious effect.	revel spliceai bayesdel
BP5	N/A	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such data are available, and this criterion is not applicable without a confirmed alternate genetic cause in the proband.
BP6	N/A	NM_002944.2:c.5825G>A is absent from ClinVar. BP6 requires a reputable source (ClinVar 3-star expert panel) to have classified the variant as benign. No ClinVar entry exists for this variant.	clinvar
BP7	N/A	BP7 applies to synonymous variants where splicing prediction algorithms predict no impact on the splice site. NM_002944.2:c.5825G>A is a missense variant (p.Arg1942Gln), not a synonymous variant, and is therefore not eligible for BP7.

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