Variant classification summary

NM_017617.5:c.7541_7542del

NOTCH1 · NP_060087.3:p.(Pro2514ArgfsTer4) · NM_017617.5

GRCh37: chr9:139390648 CAG>C · GRCh38: chr9:136496196 CAG>C

Gene: NOTCH1 Transcript: NM_017617.5

Final call

VUS

PM2 supporting

Variant details

Gene

NOTCH1

Transcript

NM_017617.5

Protein

NP_060087.3:p.(Pro2514ArgfsTer4)

gnomAD AF

1.1179471509116859e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is extremely rare in gnomAD v4.1, with grpmax FAF 7.64e-06 and zero homozygotes.

Final determination: Generic ACMG/AMP 2015 fallback rules classify the variant as VUS because one supporting criterion alone satisfies none of the pathogenic, likely pathogenic, benign, or likely benign combinations.

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	Not met: the exon 34 frameshift ends at residue 2517 instead of 2556 and removes the PEST degron, producing prolonged NOTCH1 activation rather than a demonstrated null allele.	PMID:25741868 PMID:29998084 pvs1_variant_assessment
PS1	N/A	Not applicable: PS1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no documented germline de novo finding with both maternity and paternity confirmed and no family-history information is available.	PMID:30087429 PMID:29998084
PS3	Not assessed	Not assessed: exact-variant evidence is limited to sequencing detection, while no validated functional assay result for p.P2514Rfs*4 is available.	PMID:30087429 PMID:29998084 PMID:25564152 PMID:19604236
PS4	Not assessed	Not assessed: 2/12 CLL patients carried the exact variant, but no matched unaffected-control cohort supports the required OR >5.0 with a confidence interval excluding 1.0.	PMID:30087429 PMID:29998084 gnomad_v4
PM1	N/A	Not applicable: PM1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: gnomAD v4.1 grpmax FAF is 7.64e-06, below the supplied PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: no pathogenic allele, recessive inheritance, or parental/offspring phase testing establishes this variant in trans.	PMID:30087429 PMID:29998084
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: PM5 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no germline case is documented as assumed de novo without confirmed maternity and paternity.	PMID:30087429 PMID:29998084
PP1	Not assessed	Not assessed: no affected relatives, informative meioses, or familial genotype-phenotype cosegregation data are reported.	PMID:30087429 PMID:29998084
PP2	N/A	Not applicable: PP2 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
PP3	N/A	Not applicable: the c.7541_7542del frameshift is outside PP3's missense or intronic/synonymous/splice-region computational scope.
PP4	Not met	Not met: CLL is genetically heterogeneous, and the available records provide no highly specific patient phenotype or family history for a single-gene disease.	PMID:30087429 PMID:29998084 PMID:22237449
PP5	Not met	Not met: ClinVar has zero expert-panel submissions for the exact variant, and all three germline laboratory submissions classify it as uncertain significance.	clinvar PMID:30087429 PMID:29998084
BA1	Not met	Not met: gnomAD grpmax FAF is 7.64e-06, far below the 0.05 BA1 threshold, with no qualifying high-frequency population signal.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: gnomAD v4.1 grpmax FAF is 7.64e-06, below the generic 0.01 BS1 threshold and not evidence of excess disease frequency.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not assessed	Not assessed: gnomAD shows zero homozygotes, but no phenotype-reviewed healthy adult individual is documented for the BS2 inheritance and penetrance requirements.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: sequencing confirms the exact deletion, but no validated assay demonstrates preserved NOTCH1 function or normal splicing.	PMID:30087429 PMID:29998084 PMID:25564152 PMID:19604236
BS4	Not assessed	Not assessed: no informative affected relatives lacking the variant or other familial non-segregation evidence is documented.	PMID:30087429 PMID:29998084
BP1	N/A	Not applicable: BP1 requires a missense variant, and this is a frameshift variant.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no phased pathogenic variant in cis or trans is documented for this germline case.	PMID:30087429 PMID:29998084
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a frameshift variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4 is excluded for this frameshift, regardless of its SpliceAI max delta score of 0.007.
BP5	Not assessed	Not assessed: the records do not establish an alternate molecular basis for disease in a case carrying the exact variant.	PMID:30087429 PMID:29998084
BP6	Not met	Not met: no exact-variant ClinVar expert-panel submission reports benign or likely benign, while all three laboratory submissions report uncertain significance.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a frameshift variant.	generic_acmg_combination_rules

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