NM_017617.5:c.5353G>T

NOTCH1 · NP_060087.3:p.(Glu1785Ter) · NM_017617.5

GRCh37: chr9:139396755 C>A · GRCh38: chr9:136502303 C>A

Gene: NOTCH1 Transcript: NM_017617.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

NOTCH1

Transcript

NM_017617.5

Protein

NP_060087.3:p.(Glu1785Ter)

gnomAD AF

0.0 (v4.1)

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_017617.5:c.5353G>T (NP_060087.3:p.Glu1785Ter) is a nonsense variant in exon 28 of 34 in NOTCH1, predicted to result in premature termination and nonsense-mediated decay, triggering loss of function. NOTCH1 loss of function is an established disease mechanism for autosomal dominant Adams-Oliver syndrome and congenital heart defects, with ClinGen haploinsufficiency score 3 (PVS1).

The variant is absent from gnomAD v2.1 and v4.1 (0/1,612,390 alleles) and from all population subpopulations, meeting PM2.

No case reports, segregation data, de novo observations, or functional studies specific to this variant were identified. The variant is absent from ClinVar. Five OncoKB-linked publications discuss NOTCH1 loss-of-function in somatic squamous cell carcinomas but none mention this specific variant.

Under ACMG/AMP 2015 combination rules, one very strong (PVS1) and one moderate (PM2) criterion yields a classification of Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	NM_017617.5:c.5353G>T is a nonsense variant (NP_060087.3:p.Glu1785Ter) in exon 28 of 34, predicted to trigger nonsense-mediated decay (PTC >55nt upstream of the final exon-exon junction). NOTCH1 has an established loss-of-function disease mechanism (autosomal dominant Adams-Oliver syndrome and congenital heart defects), with ClinGen haploinsufficiency score 3 (sufficient evidence). Under PMC6185798, a nonsense variant in a gene with established LoF disease mechanism qualifies for PVS1 at full strength. The variant lies upstream of the PEST domain (residues ~2400-2555), where population-tolerant truncations have been observed; this is not a region of concern for PVS1 downgrade.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	Not met	PS1 applies when the same amino acid change has been established as pathogenic via a different nucleotide substitution. No prior pathogenic variant creating a stop at codon 1785 (E1785*) was identified in ClinVar or the literature.
PS2	Not met	No de novo observation of NM_017617.5:c.5353G>T with confirmed parentage has been reported. While de novo NOTCH1 variants are documented in Adams-Oliver syndrome (Stittrich et al. 2014), this specific variant has not been observed as de novo.
PS3	Not met	No well-established in vitro or in vivo functional studies have been performed specifically on NM_017617.5:c.5353G>T (p.E1785*) in a germline context. OncoKB annotation of Likely Oncogenic reflects somatic cancer context, not germline functional validation; this does not substitute for PS3-level functional evidence under ACMG/AMP.
PS4	Not met	No case-control studies, cohort reports, or individual case reports have identified NM_017617.5:c.5353G>T in affected individuals. The variant is absent from ClinVar, and no published clinical observations were found.
PS5	Not met	No reputable source (ClinVar, clinical laboratory, or published report) has classified NM_017617.5:c.5353G>T as pathogenic. The variant is absent from ClinVar. OncoKB Likely Oncogenic annotation is a somatic cancer resource and does not qualify as a germline diagnostic classification source.
PM1	Not met	Residue E1785 does not lie within a statistically significant mutational hotspot per Cancer Hotspots. No CSPEC/VCEP-defined critical functional domain encompasses this residue for NOTCH1. Codon 1785 falls in the intracellular domain but is not within a domain with established clustering of pathogenic germline missense variants.
PM2	Met	NM_017617.5:c.5353G>T is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (0/1,612,390 alleles). Under generic ACMG/AMP rules, PM2 is met when a variant is absent from large population databases or present at an allele frequency <0.1%.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 applies to missense variants at the same codon where a different pathogenic missense change is established. NM_017617.5:c.5353G>T is a nonsense variant. No PM5 candidate comparators were identified.
PM6	Not met	No observation of NM_017617.5:c.5353G>T as a de novo event (with or without confirmed parentage) has been reported.
PP1	Not met	No published segregation data available for NM_017617.5:c.5353G>T in families with multiple affected members.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_017617.5:c.5353G>T is a nonsense variant, not a missense change.
PP3	N/A	PP3 applies to missense variants where multiple lines of computational evidence support a deleterious effect. NM_017617.5:c.5353G>T is a nonsense variant creating a premature termination codon; the deleterious nature of loss-of-function is already captured by PVS1. Computational predictors are not informative for this variant type. BayesDel score 0.66 is noted but not used to apply PP3 to a nonsense variant.
PP4	Not met	No patient phenotype or family history data are available for NM_017617.5:c.5353G>T. PP4 requires the variant to be identified in a patient with a phenotype highly specific for the gene/disease.
PP5	Not met	No reputable source (e.g., clinical diagnostic laboratory, ClinVar) has reported NM_017617.5:c.5353G>T as pathogenic. The variant is absent from ClinVar.
BA1	Not met	NM_017617.5:c.5353G>T has an allele frequency of 0.0 in gnomAD v4.1, well below the BA1 threshold of >1% (or >5%).	gnomad_v4
BS1	Not met	NM_017617.5:c.5353G>T has an allele frequency of 0.0, well below the BS1 threshold of >0.3% under generic ACMG rules.	gnomad_v4
BS2	Not met	BS2 requires observation in a healthy adult for a fully penetrant dominant disorder. NM_017617.5:c.5353G>T has not been observed in any population database (0 alleles in gnomAD), and no healthy adult carriers have been reported.
BS3	Not met	No well-established functional studies demonstrate a neutral or benign effect for NM_017617.5:c.5353G>T. OncoKB annotation indicates a likely loss-of-function effect, which is consistent with a damaging impact rather than a benign one. The somatic cancer literature (HNSCC, SCC) supports NOTCH1 as a tumor suppressor where truncating mutations are pathogenic in a somatic context.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease. The variant is absent from population databases, so no unaffected carrier data exists.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_017617.5:c.5353G>T is itself a truncating (nonsense) variant.
BP2	Not met	No observation of NM_017617.5:c.5353G>T in trans with a known pathogenic NOTCH1 variant in a healthy individual. NOTCH1 is an autosomal dominant gene; BP2 would require observation in trans with a pathogenic variant without clinical manifestations.
BP4	N/A	BP4 applies to missense variants with multiple lines of computational evidence suggesting no impact. NM_017617.5:c.5353G>T is a nonsense variant creating a premature termination codon; the functional consequence (loss of function) is unequivocal regardless of computational predictions.
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such observation has been reported for NM_017617.5:c.5353G>T.
BP6	Not met	No reputable source has reported NM_017617.5:c.5353G>T as benign. The variant is absent from ClinVar.
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_017617.5:c.5353G>T is a nonsense (stop-gain) variant.

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