NM_014159.6:c.850delT

SETD2 · NP_054878.5:p.(Ser284ProfsTer17) · NM_014159.6

GRCh37: chr3:47165275 GA>G · GRCh38: chr3:47123785 GA>G

Gene: SETD2 Transcript: NM_014159.6

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

SETD2

Transcript

NM_014159.6

Protein

NP_054878.5:p.(Ser284ProfsTer17)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_014159.6:c.850del (p.Ser284ProfsTer17) is a frameshift null variant in SETD2, a gene where germline loss of function is an established mechanism for autosomal dominant overgrowth syndrome (Sotos-like).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00 across all populations).

PVS1 (Very Strong) and PM2 (Moderate) are met. Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), one Very Strong criterion plus one Moderate criterion supports a classification of Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	NM_014159.6:c.850del is a frameshift variant in exon 3 of 20, producing a premature termination codon at p.Ser284ProfsTer17, well upstream of the NMD boundary. SETD2 germline loss of function is an established disease mechanism for autosomal dominant overgrowth syndrome (Sotos-like). Under the ClinGen SVI PVS1 framework (PMC6185798), this null variant meets PVS1 at full strength.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies only when the variant changes the same amino acid residue as a known pathogenic missense variant. This is a frameshift variant, not a missense change.
PS2	Not assessed	No de novo data are available for this variant. PS2 requires a confirmed de novo observation in a patient with disease and no family history.
PS3	Not met	Three publications (PMID:23417712, PMID:24509477, PMID:25728682) discuss SETD2 mutations in somatic cancer contexts but none mention NM_014159.6:c.850delT. No in vitro or in vivo functional studies specific to this variant were identified.
PS4	Not assessed	No case-control or cohort data available for this variant. PS4 requires a statistically significant enrichment of the variant in affected individuals compared to controls.
PS5	Not assessed	This variant is absent from ClinVar, so no clinically validated pathogenic assertion by an alternative source is available to support PS5.
PM1	Not met	No statistically significant mutational hotspot or well-established functional domain encompassing codon 284 was identified. Cancer Hotspots analysis is negative. The three OncoKB-flagged publications discuss SETD2 broadly but do not establish a germline disease-critical domain at this residue.
PM2	Met	NM_014159.6:c.850delT is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.00). Under generic ACMG/AMP, absence from large population cohorts with allele frequency <0.1% meets PM2 at moderate strength.	gnomad_v2 gnomad_v4 gnomad_canada
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants causing protein length change. This is a frameshift variant producing a premature termination codon, which is assessed under PVS1, not PM4.
PM5	N/A	PM5 requires a different missense change at the same amino acid position that is known to be pathogenic. This variant is a frameshift, and no eligible same-residue comparator variants could be harvested.
PM6	Not assessed	No de novo data are available for this variant. PM6 requires a confirmed de novo observation with confirmed maternity/paternity.
PP1	Not met	No segregation data are available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members.
PP2	N/A	PP2 applies only to missense variants in genes where missense variants are a common mechanism and benign missense variation is rare. This is a frameshift variant.
PP3	N/A	In silico prediction tools (REVEL, BayesDel) are not applicable to frameshift variants and returned no scores. SpliceAI predicts no splice impact (max delta score 0.00). No computational evidence supports pathogenicity.	spliceai
PP4	Not assessed	No patient phenotype or clinical data are available for this variant. PP4 requires the variant to be observed in a patient whose phenotype or family history is highly specific for the disease.
PP5	Not assessed	This variant is absent from ClinVar. No reputable source has independently classified this variant as pathogenic.
BA1	Not met	This variant is absent from all gnomAD populations (allele frequency 0.00). BA1 requires an allele frequency >1% in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all gnomAD populations (allele frequency 0.00). BS1 requires an allele frequency >0.3% and does not apply to absent variants.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data are available regarding observation of this variant in healthy individuals. BS2 requires the variant to be observed in a healthy adult individual for a fully penetrant disorder at an early age.
BS3	Not met	No in vitro or in vivo functional studies specific to NM_014159.6:c.850delT were identified. The three publications flagged by OncoKB discuss SETD2 mutations in cancer generally but none contain variant-specific functional data.
BS4	Not assessed	No segregation data are available for this variant. BS4 requires a lack of segregation with disease in affected family members.
BP1	N/A	BP1 applies when a missense variant in a gene is observed where a different missense at the same codon is known to be the primary pathogenic mechanism. This is a frameshift variant.
BP2	Not assessed	No data are available regarding observation of this variant in trans with a pathogenic variant. BP2 requires the variant to be observed in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a frameshift variant.
BP4	Not assessed	In silico prediction tools (REVEL, BayesDel) are not available for frameshift variants. SpliceAI predicts no splice impact (max delta 0.00). BP4 cannot be reliably applied without variant-type-appropriate computational evidence.	spliceai
BP5	Not assessed	No data are available regarding observation of this variant in a case with an alternate molecular basis for disease. BP5 requires the variant to be observed in a patient with an alternative molecular cause confirmed.
BP6	Not assessed	This variant is absent from ClinVar. BP6 requires a reputable source to have classified the variant as benign.
BP7	N/A	BP7 applies only to synonymous variants where splicing prediction algorithms predict no impact. This is a frameshift variant.

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