Variant classification summary

NM_024408.3:c.5625del

NOTCH2 · NP_077719.2:p.(Thr1876LeufsTer54) · NM_024408.3

GRCh37: chr1:120462090 TC>T · GRCh38: chr1:119919467 TC>T

Gene: NOTCH2 Transcript: NM_024408.3

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

NOTCH2

Transcript

NM_024408.3

Protein

NP_077719.2:p.(Thr1876LeufsTer54)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 (Very Strong): frameshift p.(Thr1876LeufsTer54) predicted to trigger nonsense-mediated decay in NOTCH2, which has an established loss-of-function disease mechanism.

2

PM2 (Moderate): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

3

Combined under ACMG/AMP 2015 rules, PVS1 (Very Strong) plus PM2 (Moderate) supports a final classification of Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 combination rule: 1 PVS1 (very strong) + 1 PM (moderate) evidence combination yields a Likely Pathogenic classification.

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	Met (Very Strong): frameshift p.(Thr1876LeufsTer54) predicted to trigger nonsense-mediated decay in NOTCH2, which has an established loss-of-function disease mechanism.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment PMID:16773578
PS1	N/A	Not applicable: frameshift variant produces no altered amino acid to compare against a previously pathogenic change.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband phenotype, parental genotypes, or de novo testing results were available.	final_classification_framework
PS3	Not assessed	Not assessed: no published functional assay data for this specific variant were available.
PS4	Not assessed	Not assessed: no case-control or affected-versus-control data for this variant were available.
PM1	N/A	Not applicable: frameshift variant leaves no altered residue to evaluate for mutational hotspot or critical-domain membership.	generic_acmg_combination_rules
PM2	Met	Met (Moderate): absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: NOTCH2-related disease is autosomal dominant, so no recessive trans-allele evidence applies.
PM4	N/A	Not applicable: frameshift variant causes no in-frame protein length change to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: frameshift produces no missense change to compare with a pathogenic missense at the same residue.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no de novo occurrence or parental testing results were reported.	final_classification_framework
PP1	Not assessed	Not assessed: no pedigree or segregation data were available.	final_classification_framework
PP2	N/A	Not applicable: criterion applies to missense variants; this is a frameshift.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.173 is below the ~0.2 high-confidence splice-altering threshold.	spliceai
PP4	Not assessed	Not assessed: no proband phenotype or diagnostic findings were available to evaluate phenotype specificity.
PP5	Not assessed	Not assessed: the exact variant has no ClinVar record with an expert-panel pathogenic assertion.	clinvar
BA1	Not met	Not met: absent from all queried population databases, so the high-frequency benign threshold is not reached.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: absent from population databases, so the variant's frequency cannot exceed the disorder-expected threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observations of the variant in healthy adults were available.
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal function were available.
BS4	Not assessed	Not assessed: no pedigree or non-segregation observations were available.	final_classification_framework
BP1	N/A	Not applicable: criterion applies to missense variants; this is a frameshift in a truncating-disease gene.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phase determination or observation with a second pathogenic variant was available.
BP3	N/A	Not applicable: criterion applies to in-frame indels in repetitive regions; this is a frameshift.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: SpliceAI max delta 0.173 is too high to support the ~0.1 no-splice-impact benign threshold.	spliceai
BP5	Not assessed	Not assessed: no alternative molecular diagnosis or phenotype attribution was provided.
BP6	Not assessed	Not assessed: the exact variant has no ClinVar record with an expert-panel benign assertion.	clinvar
BP7	N/A	Not applicable: criterion applies to synonymous variants; this frameshift alters the protein sequence.	generic_acmg_combination_rules

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.