NOTCH1

Final classification

Likely Pathogenic

NOTCH1 c.5353G>T · p.Glu1785Ter

NOTCH1

Gene

NOTCH1

Transcript

NM_017617.5

HGVS · transcript:coding

NM_017617.5:c.5353G>T

Consequence

N/A

GRCh38

chr9:136502303 C>A

GRCh37

chr9:139396755 C>A

Basis 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. ▾

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

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

PVS1 + PM2 → Likely Pathogenic

1 pvs1_variant_assessmentpvs1_gene_contextpvs1_generic_framework ↗

2 gnomad_v2 ↗gnomad_v4 ↗

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 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

Population frequency

Overall AF

Not observed

Homozygotes

Not observed in any ancestry group across 9 populations in gnomAD 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).

“

Absent from gnomAD v2.1.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.66.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Literature · 5 PMIDs triaged · 5 high-priority

5papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

1657403 ↗ functional

Specific EGF repeats of Notch mediate interactions with Delta and Serrate: implications for Notch as a multifunctional receptor.

The neurogenic loci Notch and Delta, which both encode EGF-homologous transmembrane proteins, appear to function together in mediating cell-cell communication and have been shown to interact at the cell surface in vitro. To examine the role of the EGF repeats in this interaction, we performed an extensive deletion mutagenesis of the extracellular domain of Notch. We find that of the 36 EGF repeats

BS3PM1PS3

21798893 ↗ functional

The mutational landscape of head and neck squamous cell carcinoma.

Head and neck squamous cell carcinoma (HNSCC) is a common, morbid, and frequently lethal malignancy. To uncover its mutational spectrum, we analyzed whole-exome sequencing data from 74 tumor-normal pairs. The majority exhibited a mutational profile consistent with tobacco exposure; human papillomavirus was detectable by sequencing DNA from infected tumors. In addition to identifying previously kno

BS3PM1PS3

21798897 ↗ functional

Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1.

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide. To explore the genetic origins of this cancer, we used whole-exome sequencing and gene copy number analyses to study 32 primary tumors. Tumors from patients with a history of tobacco use had more mutations than did tumors from patients who did not use tobacco, and tumors that were negative for human papillomav

BS3PM1PS3

22006338 ↗ functional

Loss-of-function mutations in Notch receptors in cutaneous and lung squamous cell carcinoma.

Squamous cell carcinomas (SCCs) are one of the most frequent forms of human malignancy, but, other than TP53 mutations, few causative somatic aberrations have been identified. We identified NOTCH1 or NOTCH2 mutations in ~75% of cutaneous SCCs and in a lesser fraction of lung SCCs, defining a spectrum for the most prevalent tumor suppressor specific to these epithelial malignancies. Notch receptors

BS3PM1PS3

24651013 ↗ functional

From fly wings to targeted cancer therapies: a centennial for notch signaling.

Since Notch phenotypes in Drosophila melanogaster were first identified 100 years ago, Notch signaling has been extensively characterized as a regulator of cell-fate decisions in a variety of organisms and tissues. However, in the past 20 years, accumulating evidence has linked alterations in the Notch pathway to tumorigenesis. In this review, we discuss the protumorigenic and tumor-suppressive fu

BS3PM1PS3

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots