Variant classification summary

NM_017617.5:c.5885G>A

NOTCH1 · NP_060087.3:p.(Arg1962His) · NM_017617.5

GRCh37: chr9:139395053 C>T · GRCh38: chr9:136500601 C>T

Gene: NOTCH1 Transcript: NM_017617.5

Final call

VUS

PM2 supporting

Variant details

Gene

NOTCH1

Transcript

NM_017617.5

Protein

NP_060087.3:p.(Arg1962His)

gnomAD AF

3.1021141528374416e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): present in only 5 of 1,611,804 gnomAD v4.1 alleles (AF 0.00031%) with no homozygotes, consistent with rarity in population databases.

2

Only PM2 (Supporting) was met; no ACMG/AMP 2015 combination rule for Pathogenic, Likely Pathogenic, Benign, or Likely Benign is satisfied, so the variant is classified as VUS.

Final determination: Generic ACMG/AMP 2015 fallback rules require at least a Likely Pathogenic-level or Likely Benign-level combination (e.g., 1 PVS1+1PM, 1PS+1PM, 3PM, 1BS+1BP, 2BP); with only PM2 (supporting) met, no pathogenic or benign combination threshold is reached, 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	N/A	Not applicable: this missense substitution does not produce a null allele, so the null-variant criterion cannot apply.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no previously classified pathogenic variant producing the same amino acid change at this codon was identified.	clinvar
PS2	Not assessed	Not assessed: no de novo occurrence could be evaluated because no parental genotypes or proband phenotype were available.
PS3	Not assessed	Not assessed: no functional or biochemical assay data for p.Arg1962His were available.
PS4	Not assessed	Not assessed: no affected-case series, case-control dataset, or enrichment analysis for this variant was available.
PM1	Not assessed	Not assessed: residue 1962 is not in a statistically significant hotspot, and no domain annotation was available.	oncokb
PM2	Met	Met (Supporting): found in only 5 of 1,611,804 gnomAD v4.1 alleles (AF 0.00031%), with no homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no affected proband with a second pathogenic NOTCH1 variant or phase data was identified.	clinvar
PM4	N/A	Not applicable: missense substitution does not alter protein length, so this criterion cannot apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic variant at codon 1962 was available to serve as a comparator.	pm5_candidates clinvar
PM6	Not assessed	Not assessed: no de novo occurrence or parental testing result was available.
PP1	Not assessed	Not assessed: no pedigree, relative genotypes, or informative meioses were provided.
PP2	Not assessed	Not assessed: no gene-specific missense constraint data were available to evaluate this criterion.
PP3	Not met	Not met: REVEL 0.5 falls between the PP3 threshold (>=0.644) and the BP4 threshold (<=0.290).	revel spliceai
PP4	Not assessed	Not assessed: no phenotype for the tested individual was provided, so phenotype specificity could not be evaluated.
PP5	Not met	Not met: no ClinVar record exists for this exact variant, so no expert-panel pathogenic assertion was available.	clinvar
BA1	Not met	Not met: the highest population frequency is 0.00645%, far below the stand-alone benign frequency range.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the highest observed frequency (0.01704%) does not exceed the benign-supporting frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no phenotype-ascertained healthy adult carriers were identified.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional studies were available to evaluate whether the variant has no damaging effect.
BS4	Not assessed	Not assessed: no affected relative lacking the variant or other non-segregation observation was provided.
BP1	Not assessed	Not assessed: no gene-specific data establishing a truncating-predominant mechanism of disease was available.
BP2	Not assessed	Not assessed: no observation of this variant in cis or trans with a pathogenic NOTCH1 variant was available.	clinvar
BP3	N/A	Not applicable: missense substitution does not alter protein length in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.5 does not fall below the BP4 supporting threshold (<=0.290).	revel spliceai
BP5	Not assessed	Not assessed: no affected individual or independently established alternative molecular diagnosis was provided.
BP6	Not met	Not met: no ClinVar record exists for this exact variant, so no expert-panel benign assertion was available.	clinvar
BP7	N/A	Not applicable: this criterion applies to synonymous variants only, and this is a missense substitution.	generic_acmg_combination_rules

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