Variant classification summary

NM_014159.6:c.6631G>T

SETD2 · NP_054878.5:p.(Gly2211Ter) · NM_014159.6

GRCh37: chr3:47098643 C>A · GRCh38: chr3:47057153 C>A

Gene: SETD2 Transcript: NM_014159.6

Final call

Likely Pathogenic

PVS1 very strong PM2 supporting

Variant details

Gene

SETD2

Transcript

NM_014159.6

Protein

NP_054878.5:p.(Gly2211Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Likely Pathogenic: the premature stop in exon 15 of 19 is expected to undergo nonsense-mediated decay, supporting PVS1 at very strong strength.

2

Likely Pathogenic: absence from gnomAD v2.1 and v4.1 supports PM2 at supporting strength.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus one supporting criterion supports 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 at very strong: c.6631G>T creates p.(Gly2211Ter) in exon 15 of 19, with four downstream exons and expected nonsense-mediated decay.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband-level parental testing, maternity or paternity confirmation, phenotype, or de novo observation is documented for this variant.
PS3	Not assessed	Not assessed: no reviewed study tested p.Gly2211Ter in a controlled functional assay, and gene-level effects of other SETD2 truncations cannot establish PS3.	PMID:23417712 PMID:24509477 PMID:25728682
PS4	Not assessed	Not assessed: no exact-variant affected-case/control enrichment or case-count evidence was available.
PM1	N/A	PM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM2	Met	Met at supporting strength: the variant is absent from gnomAD v2.1 and v4.1, including the available non-cancer subset checks.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no affected proband, second pathogenic variant, parental testing, or phase observation is available to establish the required in-trans evidence.
PM4	N/A	PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no affected individual with an assumed de novo variant and unconfirmed parental relationships is documented for NM_014159.6:c.6631G>T.
PP1	Not assessed	Not assessed: zero informative meioses or affected and unaffected relatives with both phenotype and variant genotype are reported for cosegregation.
PP2	N/A	PP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
PP3	N/A	Not applicable: c.6631G>T is a nonsense truncating variant, outside PP3's missense and splice-region/intronic scope.
PP4	Not assessed	Not assessed: no patient phenotype or disease-specific clinical feature match was provided for this variant.
PP5	Not met	Not met: ClinVar has no exact-variant expert-panel Pathogenic or Likely pathogenic assertion for c.6631G>T.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than exceeding the generic BA1 frequency threshold of >5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, with no observed frequency greater than expected for disease.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no unaffected homozygote or multiple unaffected carriers are reported in the available population data.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no reviewed study tested p.Gly2211Ter and showed preserved SETD2 function in a validated assay with appropriate controls.	PMID:23417712 PMID:24509477 PMID:25728682
BS4	Not assessed	Not assessed: no informative unaffected relatives with reliable phenotype evaluation and confirmed absence of the variant are documented.
BP1	N/A	BP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	generic_acmg_combination_rules
BP2	Not assessed	Not assessed: no second pathogenic variant or parental phase data establishes the cis/trans configuration required for BP2.
BP3	N/A	BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: c.6631G>T is a nonsense truncating variant, outside BP4's missense and splice-region/intronic scope.
BP5	Not assessed	Not assessed: no patient-level alternative molecular diagnosis was available to support BP5.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign assertion for c.6631G>T.	clinvar
BP7	N/A	BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_014159.6:c.6631G>T in SETD2 is a nonsense substitution introducing a premature stop codon predicted to produce NP_054878.5:p.(Gly2211Ter). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.	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.