NM_017617.5:c.5081A>G

NOTCH1 · NP_060087.3:p.(Gln1694Arg) · NM_017617.5

GRCh37: chr9:139397720 T>C · GRCh38: chr9:136503268 T>C

Gene: NOTCH1 Transcript: NM_017617.5

Final call

VUS

PM1 moderate PM2 supporting BP4 supporting

Variant details

Gene

NOTCH1

Transcript

NM_017617.5

Protein

NP_060087.3:p.(Gln1694Arg)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_017617.5:c.5081A>G (p.Gln1694Arg) is a missense variant in the NOTCH1 gene encoding the notch receptor 1.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_supporting).

The variant lies within the heterodimerization (HD) domain of the NOTCH1 negative regulatory region (NRR), a well-characterized functional domain critical for maintaining receptor autoinhibition. Pathogenic missense variants in this domain are established in both germline cardiovascular disease and somatic cancers (PM1).

Multiple lines of computational evidence suggest no deleterious effect: REVEL score 0.143, BayesDel score -0.403628, and SpliceAI max delta 0.02 (BP4).

ClinVar classifies this variant as Uncertain significance with a single submitter (Ambry Genetics); no expert panel review is available, and the linked publications do not mention this specific variant.

No functional studies (PS3/BS3), segregation data (PP1/BS4), de novo observations (PS2/PM6), or case-control data (PS4) are available for this variant.

Applying generic ACMG/AMP 2015 combination rules: 1 moderate pathogenic (PM1) + 1 supporting pathogenic (PM2_supporting) versus 1 supporting benign (BP4) is consistent with a classification of Uncertain Significance.

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 variant (c.5081A>G, p.Gln1694Arg) and does not fall into the null-variant categories (nonsense, frameshift, or canonical ±1,2 splice consensus) defined by the ClinGen PVS1 framework (PMC6185798). The variant_bucket is 'other' and apply_generic_pvs1_framework is false.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not assessed	No comparator variant with a different nucleotide change at the same codon producing the same amino acid change (p.Gln1694Arg) was identified in the case materials. PS1 requires an established pathogenic comparator meeting this criterion.
PS2	Not met	No de novo data were identified for this variant. No publications report a confirmed de novo observation of NM_017617.5:c.5081A>G with maternity/paternity testing.
PS3	Not met	No variant-specific functional studies were identified for p.Gln1694Arg. OncoKB reports unknown oncogenic effect with no reviewed functional evidence. No publications with experimental functional data for this variant were found in the literature packet.	oncokb
PS4	Not met	No proband counts or case-control data are available for this variant. The single ClinVar submission (Ambry Genetics, SCV006123720) does not report proband numbers. None of the ClinVar-linked publications (PMID:20301299, PMID:24882528, PMID:25173340) mention this variant in affected individuals.	clinvar
PS5	N/A	PS5 requires a well-established pathogenic allele identified in ClinVar at the same position. NM_017617.5:c.5081A>G is classified as Uncertain significance by a single clinical laboratory (Ambry Genetics) with review status 'criteria provided, single submitter,' which does not meet the threshold for established pathogenicity.
PM1	Met	The variant p.Gln1694Arg lies within the heterodimerization (HD) domain of the NOTCH1 negative regulatory region (NRR), a well-characterized functional domain critical for maintaining the autoinhibitory conformation of the receptor. Missense mutations in the NRR/HD domain are established as pathogenic in both germline cardiovascular disease (Adams-Oliver syndrome, aortic valve disease 1) and somatic cancers (T-ALL). The variant is absent from gnomAD population databases, consistent with lack of benign variation in this domain.	gnomad_v2 gnomad_v4 gnomad_canada
PM2	Met	The variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada, meeting the allele frequency threshold of <0.1% for PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants (different amino acid change at position 1694 classified as pathogenic) were identified. The PM5 candidate search returned zero candidates; classic same-residue PM5 semantics could not be confirmed.
PM6	Not assessed	PM6 requires a de novo observation confirmed by maternity/paternity testing. No such data were identified for this variant in any of the reviewed sources.
PP1	Not met	No cosegregation data are available for this variant. No family studies reporting segregation of NM_017617.5:c.5081A>G with disease were identified.
PP2	Not assessed	PP2 requires the variant to be a missense change in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. While pathogenic NOTCH1 missense variants are well-documented, specific missense constraint metrics (e.g., gnomAD Z-score or missense oe ratio) were not available in the evidence brief for this assessment.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect: REVEL score 0.143 (well below the 0.5 threshold), BayesDel score -0.403628 (negative/add-benign prediction), and SpliceAI max delta score 0.02 (no predicted splice impact). These in silico data do not meet the threshold for PP3.	revel bayesdel spliceai
PP4	Not met	No specific phenotype or clinical data are available for the proband(s) carrying this variant. The single ClinVar submission does not include detailed phenotypic information for PP4 assessment.
PP5	Not met	ClinVar classification is Uncertain significance with review status 'criteria provided, single submitter.' The 3-star expert panel review threshold required for PP5 at supporting strength is not met. None of the ClinVar-linked publications (PMID:20301299, PMID:24882528, PMID:25173340) mention this specific variant. Full-text review of PMID:24882528 confirmed the variant is entirely absent from this position statement on thoracic aortic disease management.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >1% allele frequency threshold for BA1.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Does not meet the >0.3% allele frequency threshold for BS1.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data on observation of this variant in healthy adult controls. The variant is absent from gnomAD, providing no evidence for or against observation in healthy individuals at any age.
BS3	Not met	No functional studies demonstrating a neutral or benign effect were identified for this variant. While in silico predictions (REVEL 0.143, BayesDel -0.403628) suggest a tolerated/benign effect, these are computational predictions evaluated under BP4, not experimental functional evidence required for BS3.
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease are available for this variant.
BP1	Not met	BP1 requires a missense variant in a gene for which primarily truncating variants cause disease. In NOTCH1, both missense and truncating variants are well-established pathogenic mechanisms for germline cardiovascular disease (AOVD1, Adams-Oliver syndrome). The literature documents pathogenic missense variants across multiple functional domains (EGF repeats, NRR/HD, ANK repeats), and the disease mechanism is not predominantly limited to truncating variants.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in NOTCH1 was reported.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.143 (below the 0.5 threshold), BayesDel score -0.403628 (negative/add-benign prediction), and SpliceAI max delta score 0.02 (no predicted splice alteration). These concordant in silico predictions support a benign effect.	revel bayesdel spliceai
BP5	Not met	No data on this variant being found in a case with an alternate molecular basis for disease. No such reports were identified in ClinVar or the literature packet.
BP6	Not met	ClinVar classification is Uncertain significance with review status 'criteria provided, single submitter.' The 3-star expert panel review threshold required for BP6 at supporting strength is not met. The single submitter (Ambry Genetics) does not constitute a reputable source at expert panel level.	clinvar
BP7	N/A	BP7 is specific to synonymous (silent) variants. NM_017617.5:c.5081A>G is a missense variant (p.Gln1694Arg) and therefore BP7 does not apply.

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