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).1 The variant is absent from gnomAD v2.1 and v4.1 (0/1,612,390 alleles) and from all population subpopulations, meeting PM2.2 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.3
NOTCH1
Final classification
Likely Pathogenic
NOTCH1 c.5353G>T · p.Glu1785Ter
NOTCH1
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
NOTCH1 c.5353G>T
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_variant_assessmentpvs1_gene_contextpvs1_generic_framework ↗
3
generic_acmg_combination_rules
Gene diagram
· NM_017617.5 · variants mapped to exon structure
NOTCH1
NM_017617.5
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
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.
Nonsense variant (p.Glu1785Terp.E1785*) in exon 28/34NMD predicted (distance from PTC to last exon-exon junction: 2315 nt)
✓
PM2
moderate
Pathogenic
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 v2.1: absentgnomAD v4.1: 0/1612
Assessed · not applied
Pathogenic
PS1
PS1 applies when the same amino acid change has been established as pathogenic via a different nucleotide substitution.
PS2
No de novo observation of NM_017617.5:c.5353G>T with confirmed parentage has been reported.
PS3
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.
PS4
No case-control studies, cohort reports, or individual case reports have identified NM_017617.5:c.5353G>T in affected individuals.
PM1
Residue E1785 does not lie within a statistically significant mutational hotspot per Cancer Hotspots.
PM6
No observation of NM_017617.5:c.5353G>T as a de novo event (with or without confirmed parentage) has been reported.
PP1
No published segregation data available for NM_017617.5:c.5353G>T in families with multiple affected members.
PP4
No patient phenotype or family history data are available for NM_017617.5:c.5353G>T.
PP5
No reputable source (e.g., clinical diagnostic laboratory, ClinVar) has reported NM_017617.5:c.5353G>T as pathogenic.
Benign
BA1
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%).
BS1
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.
BS2
BS2 requires observation in a healthy adult for a fully penetrant dominant disorder.
BS3
No well-established functional studies demonstrate a neutral or benign effect for NM_017617.5:c.5353G>T.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
BP2
No observation of NM_017617.5:c.5353G>T in trans with a known pathogenic NOTCH1 variant in a healthy individual.
BP5
BP5 requires the variant to be found in a case with an alternate molecular basis for disease.
BP6
No reputable source has reported NM_017617.5:c.5353G>T as benign.
N/A · 6
PM5 · PP2 · PP3 · BP1 · BP4 · BP7
Research & evidence
Population frequency · supports pathogenic
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1612390 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/75052 alleles, homozygotes = 0).
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / 1,612,390
0 hom
0 hom
Not observed in any ancestry group.
+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))
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 = 0.01). BayesDel score = 0.66.
Functional
Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
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
Triaged references · 5 PMIDs not cited in assessment
1657403 ↗
Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor.
ONCOKB
21798897 ↗
Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.
ONCOKB
22006338 ↗
Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.
ONCOKB