IDH2 c.515G>A, p.Arg172Lys

Reasoning

PS3 is met at strong strength. Two independent, variant-specific studies provide convergent functional evidence for IDH2 p.Arg172Lys (NM_002168.4:c.515G>A). Ward et al. (PMID:20171147) compared wild-type and R172K IDH2 in cultured cells using cell-lysate NADPH activity assays and quantified intracellular and extracellular 2HG by GC-MS, including chiral GC-MS; R172K increased alpha-ketoglutarate-dependent NADPH consumption, produced approximately 100-fold more intracellular 2HG than vector or wild-type controls, and generated the R enantiomer. The same study detected the biochemical phenotype in leukemic cells bearing heterozygous R172K, with every examined AML sample showing a 2HG signal at least 30% of the intrasample glutamate signal. Saha et al. (PMID:25043045) independently evaluated IDH2-R172K in mouse embryonic hepatoblasts and inducible/conditional mouse models with vector and wild-type controls, showing increased 2HG, impaired hepatocyte differentiation, persistence of progenitor-like cells after liver injury, and cooperation with KrasG12D in cholangiocarcinoma-like tumor development. The variant-specific controls, orthogonal biochemical and cellular readouts, in vivo model replication, and biologically relevant neomorphic IDH2 mechanism satisfy the well-established functional-study definition.

Rule

Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Evidence considered

• Ward et al. 2010 (PMID:20171147), Results: IDH2 R172K increased alpha-ketoglutarate-dependent NADPH consumption and caused approximately 100-fold higher intracellular 2HG than vector-transfected or wild-type IDH2 controls; chiral GC-MS identified the R enantiomer.
• Ward et al. 2010 (PMID:20171147), AML sample analysis: every examined leukemic sample bearing heterozygous IDH2 R172K showed a 2HG signal at least 30% of the intrasample glutamate signal.
• Saha et al. 2014 (PMID:25043045), functional and in vivo models: IDH2-R172K increased 2HG, impaired hepatocyte differentiation, persisted as progenitor-like cells after liver injury, and cooperated with KrasG12D in cholangiocarcinoma-like tumor development.
• The studies directly examined the exact p.Arg172Lys variant corresponding to NM_002168.4:c.515G>A and used wild-type, vector, or control-model comparisons with orthogonal biochemical, cellular, histologic, and gene-expression readouts.

Sources

Reasoning

The variant is p.Arg172Lys at IDH2 residue 172. The case evidence identifies this variant as lying in a statistically significant Cancer Hotspots hotspot, and COSMIC reports the same somatic variant 467 times. PMID:21326614 independently describes IDH2 R172 as a recurrent hotspot codon and reports recurrent R172K, R172M, and R172G cancer-derived substitutions. Under generic ACMG/AMP, these observations satisfy the mutational-hotspot route to PM1; no VCEP domain table or VCEP-limited region applies.

Rule

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.

Evidence considered

• Cancer Hotspots evidence states that the variant lies in a statistically significant hotspot.
• COSMIC reports IDH2 p.R172K as COSV57468734 with a somatic count of 467.
• PMID:21326614 states that IDH2 mutations in glioma are specific for R172 and identifies R172K, R172M, and R172G as observed substitutions; the study describes R172 as a hotspot codon.
• vcep_materials.json has no VCEP for IDH2 and an empty domain_tables object, so generic ACMG/AMP PM1 governs without a VCEP-specific region restriction.

Sources

Reasoning

PM2 is met at supporting strength under the supplied generic SVI threshold. The variant is absent from gnomAD v2.1, including the reported non-cancer subset, and is present only once in gnomAD v4.1 all-comers: 1/1,614,246 alleles, total AF 6.19484266958072e-07, with zero homozygotes. This AF is below the supplied PM2 supporting threshold of <=0.0001. No VCEP or disease-specific population source governs this gene, so the default all-comers source is used; the single Ashkenazi Jewish observation is also far below the PM2 threshold and is not used to claim absence.

Rule

PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)

Evidence considered

• gnomAD v2.1 all-comers: variant absent; the reported gnomAD v2.1 non-cancer subset is also absent.
• gnomAD v4.1 all-comers: 1/1,614,246 alleles, AF 6.19484266958072e-07, homozygotes 0; the AF is below the supplied <=0.0001 PM2 supporting threshold.
• No VCEP covers IDH2 in this case, so no governing non-cancer or exome-only VCEP population source supersedes the generic all-comers default.

Sources

Reasoning

NM_002168.4:c.515G>A is a missense variant producing p.(Arg172Lys), so the governing generic rule selects the REVEL path exclusively; SpliceAI and BayesDel are not used. REVEL is 0.733, which meets the supplied generic PP3 supporting threshold of >= 0.644 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, PMID:36413997).

Rule

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• Variant consequence: missense, NM_002168.4:c.515G>A, p.(Arg172Lys); therefore REVEL is the sole applicable computational path.
• Local REVEL lookup reports score 0.733 for NC_000015.10:g.90088606C>T / NM_002168.4:c.515G>A.
• Generic PP3 supporting threshold: REVEL >= 0.644, from the supplied ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997). SpliceAI and BayesDel were not counted.

Sources

Reasoning

The variant is NP_002159.2:p.(Arg172Lys) (NM_002168.4:c.515G>A). PMID:20171147 directly reports IDH2 R172K in an AML sample and functional assays, and PMID:25043045 studies IDH2-R172K in experimental models, but neither establishes this variant as a previously established pathogenic variant under generic germline ACMG/AMP criteria. ClinVar records the exact variant as somatic oncogenic/risk factor without an expert-panel pathogenic assertion. Therefore, the required prior established pathogenic same-amino-acid observation is not met.

Rule

Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.

Evidence considered

• The normalized variant is NP_002159.2:p.(Arg172Lys), corresponding to NM_002168.4:c.515G>A.
• PMID:20171147 explicitly reports an IDH2 R172K mutation in an AML sample and describes functional effects, but does not establish a generic ACMG pathogenic classification.
• PMID:25043045 explicitly studies IDH2-R172K in mouse hepatoblast and tumor models, but reports experimental mechanistic findings rather than a pathogenic variant classification.
• ClinVar variation 375987 records the exact variant with somatic oncogenic/risk-factor submissions, no expert-panel review, and no established pathogenic assertion.

Sources

Reasoning

The variant is p.Arg172Lys. PMID:21326614 documents other cancer-derived substitutions at residue 172, including R172M and R172G, but describes them as somatic cancer mutations and does not establish either as a pathogenic variant under generic ACMG/AMP criteria. The case's comparator review found no established pathogenic same-residue comparator. Accordingly, the required different missense change at the same residue determined to be pathogenic is not met.

Rule

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

Evidence considered

• PMID:21326614 reports recurrent IDH2 R172K, R172M, and R172G cancer-derived substitutions, but does not classify R172M or R172G as pathogenic.
• pm5_candidates.json contains zero same-residue candidates and zero expert-panel or non-expert majority pathogenic/likely pathogenic candidates.
• The exact variant's ClinVar submissions are somatic oncogenic/risk-factor records without an expert-panel pathogenic assertion; they cannot establish the required pathogenic comparator.

Sources

Reasoning

The governing rule is: "Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation." The exact-variant ClinVar record is NM_002168.4(IDH2):c.515G>A (p.Arg172Lys), classified as risk factor with no assertion criteria provided and zero expert-panel submissions. Its sole audited submission is non-expert and not usable for criterion leads. The literature_pass PS4/PP5 lead, PMID:34131312, was verified not to mention IDH2 c.515G>A or p.(R172K). No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present; PP5 is not met.

Rule

Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-match audit for NM_002168.4:c.515G>A (p.Arg172Lys): overall classification risk factor, review status no assertion criteria provided, expert-panel submissions 0; the only submission is SCV002047544, a non-expert risk-factor submission without criteria.
• PMID:34131312 was the literature_pass PP5 lead, but its full-text extraction states that the paper does not mention IDH2, c.515G>A, or p.(R172K).

Sources

Reasoning

BA1 is not met. The default all-comers gnomAD v4.1 record shows 1/1,614,246 alleles, total AF 6.19484266958072e-07, and zero homozygotes; the highest observed subpopulation point estimate is 1/29,606 (3.377693710734311e-05) in Ashkenazi Jewish individuals, whose observed allele count is below the required 2,000-allele population threshold. The record supplies no grpmax FAF, and no frequency is near the >=0.05 BA1 threshold. The variant is also absent from gnomAD v2.1 and its non-cancer subset, so there is no qualifying population-frequency basis for a stand-alone benign call.

Rule

BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)

Evidence considered

• gnomAD v4.1: 1 alternate allele among 1,614,246 total alleles; total AF 6.19484266958072e-07; homozygotes 0; grpmax FAF not reported.
• gnomAD v4.1 Ashkenazi Jewish subgroup: 1/29,606 alleles, AF 3.377693710734311e-05; this subgroup has fewer than 2,000 observed alleles and therefore cannot qualify as the required filtering population for BA1/BS1.
• gnomAD v2.1 all-comers and non-cancer records report the variant as absent.

Sources

Reasoning

BS1 is not met. The default all-comers gnomAD v4.1 frequency is 6.19484266958072e-07 (1/1,614,246 alleles), far below the generic 0.01 default, and the only nonzero subgroup observation is an unqualified Ashkenazi Jewish point estimate of 3.377693710734311e-05 from 29,606 observed alleles. No grpmax FAF is reported, no qualifying population has an elevated filtering AF, and the available data do not show an allele frequency greater than expected for the disorder. A disorder-specific maximum-credible-frequency calculation is therefore unnecessary to reject this low-frequency BS1 path; prevalence, penetrance, and allelic heterogeneity cannot convert this frequency into BS1.

Rule

BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)

Evidence considered

• gnomAD v4.1: total AF 6.19484266958072e-07 from 1/1,614,246 alleles; grpmax FAF is not reported.
• The highest observed subgroup point estimate is Ashkenazi Jewish AF 3.377693710734311e-05 from 1/29,606 alleles, which is not a qualifying >=2,000-observed-allele grpmax FAF result.
• The generic BS1 default supplied for this case is >=0.01; the observed all-comers AF is approximately 16,000-fold lower than that default.
• Whiffin et al. 2017 (PMID:28518168) is the cited framework for disorder-specific maximum credible allele-frequency reasoning, but no elevated frequency requiring such a calculation is present here.

Sources

Reasoning

BS3 is not met. The available variant-specific functional studies do not show no damaging effect on protein function or splicing; instead, they demonstrate abnormal IDH2-R172K neomorphic activity. The studies report increased alpha-ketoglutarate-dependent NADPH consumption, approximately 100-fold increased intracellular 2HG, production of R-2HG, impaired hepatocyte differentiation, and disease-relevant effects in mouse models compared with vector or wild-type controls. No validated assay demonstrating preserved IDH2 function or normal splicing for this variant was identified.

Rule

Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.

Evidence considered

• Ward et al. 2010 (PMID:20171147), variant-specific biochemical assays showed abnormal IDH2-R172K activity and approximately 100-fold increased intracellular 2HG relative to vector or wild-type controls.
• Saha et al. 2014 (PMID:25043045), variant-specific hepatoblast and mouse-model experiments showed increased 2HG and impaired hepatocyte differentiation, with additional disease-relevant effects.
• These findings are inconsistent with a BS3 conclusion that well-established functional studies show no damaging effect on protein function or splicing.

Sources

Reasoning

The available evidence does not show that IDH2-related disease is caused primarily by truncating variants. Instead, the directly reviewed IDH2 literature describes recurrent missense substitutions at the Arg172 hotspot with neomorphic gain-of-function activity, including R172K, R172M, and R172G. This is inconsistent with the BP1 premise that disease is primarily caused by truncating variants, so BP1 is not met.

Rule

Missense variant in a gene for which primarily truncating variants are known to cause disease.

Evidence considered

• PMID:20171147 reports IDH2 R172K and demonstrates neomorphic 2HG-producing activity in cell-based assays.
• PMID:21326614 reports recurrent IDH2 R172 missense substitutions and concludes that shared gain of enzymatic 2HG-producing activity is important in cancer pathogenesis.
• No source in the case evidence establishes a disease context in which truncating IDH2 variants are the primary known cause.

Sources

Reasoning

NM_002168.4:c.515G>A is a missense variant, so the governing generic rule selects REVEL exclusively; SpliceAI cannot substitute for a non-benign REVEL result, and BayesDel has no generic ACMG-strength calibration. REVEL is 0.733, above the generic BP4 supporting threshold of <= 0.29 (ClinGen SVI REVEL calibration, Pejaver et al. 2022, PMID:36413997), so BP4 is not met.

Rule

Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc) ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)

Evidence considered

• Variant consequence: missense, NM_002168.4:c.515G>A, p.(Arg172Lys); therefore REVEL is the sole applicable computational path.
• Local REVEL lookup reports score 0.733 for NC_000015.10:g.90088606C>T / NM_002168.4:c.515G>A.
• Generic BP4 supporting threshold: REVEL <= 0.29, from the supplied ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997); 0.733 does not meet it. The available SpliceAI max delta 0.027 was not used because this is a missense variant, and BayesDel is not generically calibrated for this criterion.

Sources

Reasoning

The governing rule is: "Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation." The exact-variant ClinVar record is classified as risk factor with no assertion criteria provided, has zero expert-panel submissions, and contains no expert-panel Benign or Likely benign classification. The available ClinVar submission is non-expert and does not report benign significance. BP6 is not met.

Rule

Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.

Evidence considered

• ClinVar exact-match audit for NM_002168.4:c.515G>A (p.Arg172Lys): classification risk factor, no assertion criteria provided, expert-panel submissions 0, and no Benign or Likely benign expert-panel assertion; the sole submission is non-expert.

Sources

Reasoning

No documented proband-level de novo observation is available, and there is no evidence of confirmed maternity and paternity, parental testing, or absence of a family history. The PS2 definition therefore cannot be evaluated.

Rule

De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.

Evidence considered

• No proband-specific de novo result, parental genotype, maternity confirmation, paternity confirmation, or family-history assessment was documented in the available case evidence.
• The available literature extracts concern somatic IDH2 R172K observations and functional studies, not a germline de novo family study.

Still missing

• Proband phenotype and disease diagnosis
• Parental testing results
• Confirmed maternity and paternity
• Family history status

Reasoning

The governing rule is: "The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0." The literature_pass.json criteria index listed PMID:34131312 for PS4, but its full-text extraction states that the paper does not mention IDH2, c.515G>A, or p.(R172K), so it provides no case-control evidence. PMID:20171147 reports IDH2 R172K in one AML sample but provides no affected-case versus unaffected/population-control counts for this variant. gnomAD v4.1 reports 1/1,614,246 alleles overall, but no matched case frequency is available; therefore an OR and 95% CI cannot be computed. The required numeric comparison is OR > 5.0 with a 95% CI excluding 1.0, but no OR/CI is available, so PS4 cannot be assessed.

Rule

The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. ... Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.

Evidence considered

• PMID:20171147, Introduction and Results: reports "we found an IDH2 R172K mutation in an AML sample obtained from a 77 year old female"; the extracted study describes a patient sample and functional assays but no unaffected or population control comparison for this exact variant.
• PMID:34131312, Limitations of CMA: "Duplications and deletions below the detection level according to probe coverage and performance, single-nucleotide variants (SNVs) or insertions/deletions (indels) not covered by the platform, gene expression, or epigenetic modifications." The extraction searched IDH2 c.515G>A and p.(R172K) and found no mention of the variant.
• gnomAD v4.1: 1/1,614,246 alleles overall (AF 6.19484266958072e-07), with no affected-case frequency supplied; this population count alone cannot yield the required OR and 95% CI.

Still missing

• A case-control study or equivalent affected-case and matched-control counts for IDH2 c.515G>A are needed to calculate OR and its 95% CI.

Sources

Reasoning

PM3 cannot be assessed from the available evidence. IDH2 has no established recessive germline disorder or inheritance mode documented in this case, and the available variant-specific report describes a heterozygous somatic IDH2 R172K mutation in an AML sample without a pathogenic second allele, parental/offspring testing, or phase determination. Therefore, detection in trans with a pathogenic variant has not been established.

Rule

For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.

Evidence considered

• ClinVar variation 375987 records this variant as a somatic submission with a risk-factor classification and no usable clinical assertion or phase information.
• PMID:20171147 reports IDH2 R172K in an AML sample and describes leukemic cells bearing heterozygous R172K mutations, but reports no pathogenic second allele, parental/offspring testing, or trans phase.
• No evidence in the reviewed case materials establishes a recessive germline IDH2 disorder or phase for NM_002168.4:c.515G>A (p.Arg172Lys).

Still missing

• Establish the relevant germline disease and inheritance mode for IDH2.
• Document an affected proband with a second pathogenic variant and demonstrate that the two variants are in trans by parental or offspring testing.

Sources

Reasoning

No documented assumed-de novo observation is available. The case evidence does not provide parental testing, a negative family history, or other information establishing that the variant arose de novo without maternity and paternity confirmation.

Rule

Assumed de novo, but without confirmation of paternity and maternity.

Evidence considered

• No proband-specific parental testing or assumed-de-novo statement was documented in the available case evidence.
• The available literature extracts concern somatic IDH2 R172K observations and functional studies, not a germline de novo family study.

Still missing

• Proband phenotype and disease diagnosis
• Parental genotype results or an explicit assumed-de-novo report
• Family history status

Reasoning

No affected relatives, informative meioses, segregation results, or family phenotype data are documented. Accordingly, co-segregation cannot be assessed, and no evidence supports applying PP1 at any strength.

Rule

Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Evidence considered

• No family pedigree, affected-relative testing, unaffected-relative testing, or segregation analysis was documented in the available case evidence.
• The available literature extracts do not report familial segregation for NM_002168.4:c.515G>A (p.Arg172Lys).

Still missing

• Family pedigree and affected-relative phenotypes
• Genotypes of affected and unaffected relatives
• Number of informative meioses
• Evidence that the gene is definitively associated with the relevant disease

Reasoning

The available case evidence establishes that IDH2 R172 missense mutations are recurrent in somatic cancers, but it does not provide a gene-wide assessment showing both a low rate of benign missense variation and that missense variants are a common mechanism of disease in the applicable germline disease context. A single rare gnomAD observation for this variant and cancer-focused functional literature are insufficient to apply both PP2 components. The criterion is therefore not assessed.

Rule

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

Evidence considered

• gnomAD v4.1 reports the exact variant at AF 6.19484e-07 (1/1,614,246 alleles; no homozygotes), but this single-variant observation does not quantify the gene-wide benign missense rate.
• PMID:20171147 and PMID:21326614 describe recurrent somatic IDH2 missense mutations and gain-of-function biology, but do not establish the required gene-wide germline PP2 mechanism and benign-variation components.

Still missing

• Gene-wide evidence quantifying benign missense variation and confirming a common germline missense disease mechanism for IDH2.

Sources

Reasoning

The governing rule is: "Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology." The case evidence identifies the variant and gene but supplies no patient phenotype, family history, or disease-specific clinical description from which high specificity for a single genetic etiology can be judged. PP4 therefore cannot be assessed.

Rule

Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.

Still missing

• A documented patient phenotype or family history and the relevant disease-specificity assessment are needed.

Reasoning

BS2 cannot be assessed from the available evidence. The population records report allele counts and homozygote counts, but they do not identify healthy adult carriers or establish that any carrier was an unaffected adult. No inheritance model, expected penetrance, or age-of-onset information for a germline IDH2 disorder is available in the population evidence, so the required healthy-adult observation cannot be inferred from gnomAD membership or from the absence of homozygotes.

Rule

Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.

Evidence considered

• gnomAD v4.1 reports zero homozygotes among 1,614,246 total alleles and one heterozygous allele, but provides no phenotype or age-of-onset information for that carrier.
• gnomAD v2.1 reports the variant as absent; absence does not provide a healthy-adult observation.

Still missing

• A documented healthy adult carrying the variant in the relevant zygosity is required.
• The relevant germline disease inheritance model, penetrance, and expected age of onset are not established for this assessment.

Sources

Reasoning

No affected family members with documented absence of the variant are identified, and no pedigree, phenotype assessment, or segregation testing is available. Lack of segregation therefore cannot be established; the phenocopy and multilocus-family caveats also cannot be evaluated.

Rule

Lack of segregation in affected members of a family.

Evidence considered

• No affected relative with a documented negative result for NM_002168.4:c.515G>A was reported in the available case evidence.
• No family-level phenotype review was available to assess phenocopies or the possibility of more than one pathogenic variant contributing to an autosomal dominant disorder.

Still missing

• Family pedigree and affected-relative phenotypes
• Genotypes of affected relatives
• Assessment for phenocopies
• Assessment for more than one pathogenic variant in the family

Reasoning

BP2 cannot be assessed from the available evidence. The case provides no documented observation of NM_002168.4:c.515G>A in trans with a pathogenic variant in a fully penetrant dominant germline disorder and no observation of this variant in cis with a pathogenic variant. The available variant-specific evidence is somatic cancer evidence and does not establish either qualifying allelic configuration.

Rule

Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• ClinVar variation 375987 contains somatic submissions and does not provide a qualifying cis/trans allelic observation or phase data.
• PMID:20171147 reports a heterozygous somatic IDH2 R172K mutation in AML but does not report a pathogenic variant in cis or trans or establish a fully penetrant dominant germline disorder.
• No qualifying cis or trans pathogenic-variant configuration is documented in the reviewed case materials.

Still missing

• Document whether the variant occurs in cis with a pathogenic variant or in trans with a pathogenic variant in a fully penetrant dominant germline disorder.
• Provide phase testing and relevant affected-proband or inheritance data for any alleged allelic observation.

Sources

Reasoning

The governing rule is: "Variant found in a case with an alternate molecular basis for disease." The available evidence does not document a case carrying IDH2 c.515G>A with an alternate molecular diagnosis or other alternate molecular basis for the relevant disease. Somatic cancer occurrence and functional observations do not establish the BP5 requirement. BP5 cannot be assessed.

Rule

Variant found in a case with an alternate molecular basis for disease.

Still missing

• A documented case carrying IDH2 c.515G>A with an established alternate molecular basis for disease is needed.