SETD2c.850delLikely pathogenic

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Variant interpretation report

SETD2 c.850del, p.(Ser284ProfsTer17)

NM_014159.6:c.850del NP_054878.5:p.(Ser284ProfsTer17) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About SETD2

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 moderate (pathogenic)
Expert rules: Not recorded
Pipeline record: 22 Jun 2026

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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.
PM2 (moderate): 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.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

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.

PM2Moderate

PM2 · moderate

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

Not recorded

gnomAD v4.1 allele counts were not recorded for this variant.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 2 met · 6 not met · 12 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴

Evidence considered

Frameshift null variant (NM_014159.6:c.850del
NP_054878.5:p.Ser284ProfsTer17)
Exon 3 of 20
premature termination codon at ~codon 300 of 2565 — NMD predicted
SETD2 germline LoF established mechanism: overgrowth syndrome (PMID:24852293
PMID:31643139)
No evidence of exon-level biological irrelevance or population LoF enrichment

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 ModerateNM_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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AC=0
AF=0.00
gnomAD v4.1: AC=0
gnomAD-Canada v1.0: AC=0

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 6 · evaluated, threshold not reached

PS3 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. Details ▾Hide ▴

Evidence considered

Full-text review of PMID:23417712
PMID:24509477
PMID:25728682 — variant not mentioned in any

Still missing

No variant-specific functional studies available

PM1 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. Details ▾Hide ▴

Evidence considered

Cancer Hotspots: residue not significant
No germline disease-critical domain established at codon 284

PP1 No segregation data are available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members. Details ▾Hide ▴

Still missing

No segregation data available

BA1 This variant is absent from all gnomAD populations (allele frequency 0.00). BA1 requires an allele frequency >1% in any population. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.00
gnomAD v4.1: AF=0.00
gnomAD-Canada: AF=0.00

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 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. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=0.00
gnomAD v4.1: AF=0.00
gnomAD-Canada: AF=0.00

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS3 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. Details ▾Hide ▴

Evidence considered

Full-text review of PMID:23417712
PMID:24509477
PMID:25728682 — no variant-specific functional data

Still missing

No variant-specific functional studies available

Not assessed · 12 · no assessment recorded

PS2 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. Details ▾Hide ▴

Still missing

No de novo testing data available

PS4 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. Details ▾Hide ▴

Still missing

No case-count data available

PM6 No de novo data are available for this variant. PM6 requires a confirmed de novo observation with confirmed maternity/paternity. Details ▾Hide ▴

Still missing

No de novo testing data available

PP4 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. Details ▾Hide ▴

Still missing

No clinical phenotype data available

PP5 This variant is absent from ClinVar. No reputable source has independently classified this variant as pathogenic. Details ▾Hide ▴

Evidence considered

Absent from ClinVar

Still missing

Not present in ClinVar
no expert panel or reputable source classification

BS2 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. Details ▾Hide ▴

Still missing

No healthy control observation data available

BS4 No segregation data are available for this variant. BS4 requires a lack of segregation with disease in affected family members. Details ▾Hide ▴

Still missing

No segregation data available

BP2 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. Details ▾Hide ▴

Still missing

No phase data available

BP4 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. Details ▾Hide ▴

Evidence considered

REVEL/BayesDel: not applicable (indel
not SNV)
SpliceAI: max delta 0.00 — no splice impact

Sources

spliceai ↗

BP5 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. Details ▾Hide ▴

Still missing

No alternate-molecular-cause data available

BP6 This variant is absent from ClinVar. BP6 requires a reputable source to have classified the variant as benign. Details ▾Hide ▴

Evidence considered

Absent from ClinVar

Still missing

Not present in ClinVar

PS5 This variant is absent from ClinVar, so no clinically validated pathogenic assertion by an alternative source is available to support PS5. Details ▾Hide ▴

Evidence considered

Absent from ClinVar

Still missing

Not present in ClinVar

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 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. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 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. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 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. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 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. Details ▾Hide ▴

No further detail was recorded.

PP3 N/AIn 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. Details ▾Hide ▴

Evidence considered

REVEL: not applicable (indel
not SNV)
BayesDel: not applicable (indel
SpliceAI: max delta 0.00 — no predicted splice impact

Sources

spliceai ↗

BP1 N/ABP1 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. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions without a known function. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies only to synonymous variants where splicing prediction algorithms predict no impact. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: SETD2
Transcript: NM_014159.6
Coding (HGVS c.): NM_014159.6:c.850del
Protein (HGVS p.): NP_054878.5:p.(Ser284ProfsTer17)
GRCh38: chr3:47123785 GA>G
GRCh37: chr3:47165275 GA>G

Gene diagram

Every interpreted variant in SETD2, mapped onto the exon structure of NM_014159.6. Select a row to find it on the plot.

SETD2NM_014159.6

Fetching transcript structure from UCSC…

Exons

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Transcript span

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Strand

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Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in SETD2 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 Allele count data not recorded

gnomAD v2.1 Allele count data not recorded

gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -114 bp

0.000

SpliceAI acceptor gainat -412 bp

0.000

SpliceAI donor lossat -227 bp

0.000

SpliceAI donor gainat -372 bp

0.000

Pangolin splice lossmagnitude shown

-0.050

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

REVEL/BayesDel: not applicable (indel
not SNV)
SpliceAI: max delta 0.00 — no splice impact

Sources

spliceai ↗

Evidence considered

REVEL: not applicable (indel
not SNV)
BayesDel: not applicable (indel
SpliceAI: max delta 0.00 — no predicted splice impact

Sources

spliceai ↗

BP7 N/ABP7 applies only to synonymous variants where splicing prediction algorithms predict no impact. This is a frameshift variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

3 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Mutations in SETD2 and genes affecting histone H3K36 methylation target hemispheric high-grade gliomas.

Identified SETD2 mutations in a cohort of 60 pediatric high-grade gliomas using whole-exome sequencing, along with mutations in other H3K36 methylation pathway genes. Discusses SETD2 as a tumor suppressor in glioma.
Does not name this variant
PMID 23417712 ↗
Identification of functional cooperative mutations of SETD2 in human acute leukemia.

Identified biallelic SETD2 mutations cooperatively driving MLL-rearranged acute leukemia through disrupted H3K36me3 and altered gene expression. Demonstrates SETD2 as a tumor suppressor in leukemia.
Does not name this variant
PMID 24509477 ↗
SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair.

Demonstrated that SETD2 loss-of-function promotes renal cancer branched evolution through replication stress and impaired DNA repair. Shows H3K36me3 loss leads to genomic instability in ccRCC.
Does not name this variant
PMID 25728682 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar Captured ClinVar source record Open source ↗

COSMIC Captured COSMIC source record Open source ↗

Cancer hotspots Captured Cancer Hotspots source record Open source ↗

OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.