NM_024408.3:c.3570G>C

NOTCH2 · NP_077719.2:p.(Glu1190Asp) · NM_024408.3

GRCh37: chr1:120478180 C>G · GRCh38: chr1:119935557 C>G

Gene: NOTCH2 Transcript: NM_024408.3

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

NOTCH2

Transcript

NM_024408.3

Protein

NP_077719.2:p.(Glu1190Asp)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_024408.3:c.3570G>C (p.Glu1190Asp) in NOTCH2 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting a rare variant interpretation.

Multiple in silico predictors suggest no significant impact: BayesDel predicts a benign score (-0.045) and SpliceAI indicates no splicing impact (max delta 0.07).

The variant is a novel missense change at a residue not in a known functional domain or mutational hotspot. No functional studies, segregation data, or de novo reports are available.

Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting pathogenic) and BP4 (supporting benign) are both met. The single supporting pathogenic and single supporting benign criterion do not reach the threshold for Likely Pathogenic or Likely Benign.

This 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	Not met	NM_024408.3:c.3570G>C is a missense variant (p.Glu1190Asp) and does not fall into any ClinGen SVI PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 decision framework from PMC6185798 does not apply.	pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant at residue 1190 with the same amino acid change (p.Glu1190Asp) was identified. This variant is absent from ClinVar, and no literature reports an identical change at this position.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity is available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies were identified for this variant. OncoKB reports no variant-specific reviewed functional evidence (classification: Unknown Oncogenic Effect).	oncokb
PS4	Not met	No case-control or cohort data demonstrating enrichment of this variant in affected individuals is available.
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar with no submitter classifications.	clinvar
PM1	Not met	Residue 1190 does not fall within a statistically significant mutational hotspot (CancerHotspots negative). No gene-specific VCEP/ClinGen domain specification is available for NOTCH2 to support a critical functional domain assignment at this position.
PM2	Met	NM_024408.3:c.3570G>C is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP rules, absence from population databases meets PM2 at supporting strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants with established pathogenicity were identified. PM5 candidate harvesting was not possible, and no pathogenic variant at residue 1190 with a different amino acid change was found.
PM6	Not met	No de novo observation (without confirmation of paternity and maternity) is available for this variant.
PP1	Not met	No cosegregation data in affected families is available for this variant.
PP2	Not met	NOTCH2 missense constraint data are not available (HCI prior not found). Without evidence that NOTCH2 has a low rate of benign missense variation and that missense is a common disease mechanism, PP2 cannot be applied.
PP3	Not met	In silico predictions are discordant. REVEL score 0.567 is marginally above the 0.5 threshold, but BayesDel score -0.045 is below 0 (predicted benign), and SpliceAI max delta 0.07 indicates no splicing impact. Multiple lines do not consistently support a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available; the variant was assessed as a standalone laboratory finding.
PP5	Not met	No reputable source has reported this variant as pathogenic; it is absent from ClinVar.	clinvar
BA1	Not met	NM_024408.3:c.3570G>C is absent from all population databases. Allele frequency is 0.00%, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all population databases. Allele frequency is 0.00%, below the 0.3% BS1 threshold (non-VCEP).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No homozygous or hemizygous observations in healthy adults, and no trans observation with a known pathogenic variant, are available.
BS3	Not met	No well-established functional studies showing no damaging effect are available for this variant.
BS4	Not met	No segregation data showing lack of cosegregation with disease is available.
BP1	Not met	While NOTCH2 loss-of-function is a supported disease mechanism (Alagille syndrome, via NOTCH2-related disorders), missense variants have also been reported as pathogenic in Alagille syndrome. The disease mechanism is not exclusively truncating, so BP1 does not apply.	pvs1_gene_context
BP2	Not met	No observation in trans with a pathogenic variant in a dominant disorder or in cis with a pathogenic variant in a recessive disorder is available.
BP3	N/A	Variant is not an in-frame indel in a repetitive region.
BP4	Met	Multiple lines of computational evidence suggest no impact on gene product: BayesDel score -0.045 is below 0 (predicted benign) and SpliceAI max delta score 0.07 indicates no splicing impact. REVEL score 0.567 is marginally above 0.5, but the overall in silico consensus favors a benign interpretation (2 of 3 tools predict benign/no impact).	bayesdel spliceai revel
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease is available.
BP6	Not met	No reputable source has reported this variant as benign.	clinvar
BP7	N/A	c.3570G>C is a missense variant (p.Glu1190Asp), not a synonymous variant.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.