The IDH1 NM_005896.4:c.394C>T (NP_005887.2:p.(Arg132Cys)) missense variant has previously been reported in somatic cancers (COSMIC; COSV61615256, n = 1377 times), and lies in a statistically significant hotspot (cancerhotspots.org). Experimental evidence: Recombinant R132C IDH1 produced the neomorphic 2-hydroxyglutarate activity, with independent R132C cellular and ex vivo confirmation. Based on available guidelines, this variant is considered to be Likely Pathogenic.
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.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.IDH1 encodes a cytoplasmic and peroxisomal enzyme that converts isocitrate to alpha-ketoglutarate and helps produce NADPH, supporting cellular metabolism and antioxidant processes. Altered IDH1 activity is associated with several cancers, including glioma, cholangiocarcinoma, and acute myeloid leukemia. In cancer, abnormal IDH1 activity can produce D-2-hydroxyglutarate, which disrupts cellular enzymes that regulate DNA and histone modification and can promote tumor development.
The recorded framework is Generic ACMG/AMP 2015 with ClinGen SVI recommendations. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at moderate strength: recombinant R132C IDH1 produced the neomorphic 2-hydroxyglutarate activity, with independent R132C cellular and ex vivo confirmation.
Met, moderate: residue 132 is an IDH1 active-site position and a statistically significant R132 hotspot associated with gain-of-function mutations.
Met at supporting: gnomAD v3.1 non-cancer grpmax FAF is 0.0 and total AF is 6.79329e-06, below the <=0.0001 PM2 threshold.
Met at supporting strength: REVEL 0.814 exceeds the PP3 supporting threshold of >=0.644 for this missense variant.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PS3 and PM1 at moderate strength plus PM2 and PP3 at supporting strength satisfy the generic ACMG/AMP 2015 rule for 2 moderate and 2 supporting criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,613,126 alleles. Recorded AF 6.19914e-07. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
Recorded REVEL score: 0.814. Refer to the recorded PP3/BP4 rationale for interpretation.
8 Pathogenic · 1 Likely pathogenic · 1 pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV61615256, n = 1377 times).
This variant lies in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 10 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The exact variant has tissue-restricted somatic evidence in PMID:37324278, not documented germline de novo evidence.
No affected-relative segregation or non-segregation dataset is available for PP1 or BS4.
The exact variant has multiple biologically relevant, variant-specific functional findings supporting altered IDH1 activity, with the strongest direct evidence coming from recombinant enzyme assays and independent R132C cellular/ex vivo systems.
PS3 is assigned at moderate strength because the evidence is consistent across assays but lacks documented clinical diagnostic laboratory validation and inter-laboratory reproducibility; BS3 is not met because the functional findings are not benign.
No VCEP covers IDH1 in this case, so generic ACMG/AMP 2015 definitions govern.
Phenotype-prevalence criteria were adjudicated independently; no criterion was inferred from another source's final classification.
ClinVar Pathogenic/Likely pathogenic laboratory submissions were not treated as PP5, and no Benign/Likely benign expert-panel assertion was treated as BP6.
For this missense variant, the governing generic computational path is REVEL only: REVEL 0.814 supports PP3 at supporting strength and does not meet BP4; SpliceAI 0.509 and BayesDel 0.415345 were not counted for PP3/BP4.
No criteria match.
PS3 is met at moderate strength. The exact variant, IDH1 p.Arg132Cys (NM_005896.4:c.394C>T), was directly tested in multiple biologically relevant functional systems. Purified recombinant R132C IDH1 demonstrated gain-of-function NADPH-dependent reduction of alpha-ketoglutarate to 2-hydroxyglutarate, explicitly distinguishing the mutant from wild type and supporting an altered enzymatic activity (PMID:19935646). Independent cellular and ex vivo work also specifically included R132C: the endogenous R132C HT1080 model and primary R132C AML blasts showed mutant-selective pharmacologic and differentiation responses, including reduction of intracellular 2-hydroxyglutarate (PMID:29670690). These are variant-specific, biologically relevant functional results with comparator controls, but the available evidence does not establish reproducibility and robustness in a clinical diagnostic laboratory setting; therefore, the evidence is not calibrated as strong PS3.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
IDH1 p.Arg132Cys lies at residue 132, a documented active-site residue and statistically significant IDH1 R132 hotspot. PMID:19935646 describes R132 as part of the IDH1 active site and shows that R132 substitutions produce gain-of-function enzymatic activity; the Cancer Hotspots result identifies the IDH1 R132 hotspot. No VCEP-specific domain table or hotspot restriction applies because no VCEP covers IDH1.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM2 is met at supporting strength. The variant is absent from gnomAD v2.1 non-cancer exomes (0/236754) and gnomAD v2.1 all-comers exomes (0/251292). It is observed only once in gnomAD v3.1 non-cancer genomes (1/147204; AF 6.79329e-06; grpmax FAF=0.0) and once in gnomAD v4.1 all-comers (1/1613126; AF 6.19914e-07), both below the supplied PM2 supporting threshold of <=0.0001. No homozygotes are reported.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020)
The variant is a missense substitution, p.(Arg132Cys), so the generic PP3/BP4 missense path requires REVEL only; the SpliceAI result is not used for this missense assessment. REVEL is 0.814, meeting the generic PP3 supporting threshold of >= 0.644 but not the moderate threshold of >= 0.773. BayesDel is not used because no generic ACMG-strength calibration is established. Therefore PP3 is met at supporting strength.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
PS2 is not met. PMID:37324278 reports IDH1 c.394C>T (p.Arg132Cys) in ovarian juvenile granulosa cell tumor and enchondromatosis tissue, but not in the patient's peripheral blood or either parent's peripheral blood. This supports a tumor-restricted somatic occurrence rather than a germline de novo variant in a proband with the disease; therefore, the required germline de novo evidence is absent.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The reviewed variant-specific literature does not provide a case-control comparison for IDH1 c.394C>T (p.Arg132Cys). PMID:29860938 reports the variant among affected AML patients (47/78 [60%] in dose escalation and 109/180 [61%] in dose expansion), but provides no unaffected or population control count for the same comparison; PMID:37324278 is a single tumor case and is not a case-control study. gnomAD v4.1 reports 1/1,613,126 alleles overall and 1/1,179,790 European non-Finnish alleles, but the available evidence does not provide a matched affected-case frequency from a case-control cohort from which a valid OR and 95% CI can be calculated. Therefore the ACMG/AMP PS4 requirement is not met. No PS4 paper was present in literature_pass.json packet.ai_classified_papers; the criteria-index leads were checked against the available extracts and did not establish case-control evidence.
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.
PM6 is not met. The exact variant was detected in tumor and enchondromatosis tissue but was not detected in the patient's peripheral blood or either parent's peripheral blood (PMID:37324278). The available evidence therefore does not establish an assumed germline de novo variant; it instead supports a tumor-restricted somatic occurrence.
Assumed de novo, but without confirmation of paternity and maternity.
ClinVar lists IDH1 c.394C>T (p.Arg132Cys) as Pathogenic/Likely pathogenic, but the record has no expert-panel submissions and the available assertions are ordinary laboratory submissions or aggregate labels. Under the required generic handling for this group, those submissions cannot trigger PP5; no exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. No governing VCEP-specific population source applies, so the generic all-comers and available non-cancer gnomAD data were reviewed. gnomAD v2.1 non-cancer exomes show 0/236754 alleles, and gnomAD v2.1 all-comers exomes show 0/251292. gnomAD v3.1 non-cancer genomes show 1/147204 alleles (AF 6.79329e-06) with grpmax FAF=0.0; gnomAD v4.1 shows 1/1613126 total alleles (AF 6.19914e-07), with no reported grpmax FAF. The filtering AF available from gnomAD is therefore far below the generic BA1 threshold of >=0.05, and the pathogenic ClinVar consensus also makes a stand-alone benign call inappropriate without a qualifying frequency.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The variant is not present at a frequency greater than expected for the disorder in the available population data. The relevant gnomAD v3.1 non-cancer genome result has grpmax FAF=0.0, and the observed total AF is only 6.79329e-06 (1/147204); gnomAD v2.1 non-cancer exomes show 0/236754 and gnomAD v4.1 shows 1/1613126. These values are below the generic BS1 default threshold of >=0.01, with no elevated ancestry-specific frequency requiring a maximum-credible-frequency calculation.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
BS3 is not met. The exact IDH1 p.Arg132Cys variant has functional results showing altered, neomorphic enzyme activity rather than no damaging effect: purified R132C protein reduced alpha-ketoglutarate to 2-hydroxyglutarate, and independent R132C cellular/ex vivo assays demonstrated mutant-specific biological activity. These findings are inconsistent with the BS3 requirement for well-established functional studies showing no damaging effect on protein function or splicing. No well-established benign functional assay result for this variant was identified.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense substitution, p.(Arg132Cys), so BP4 must be assessed through the REVEL path only; the SpliceAI result is not used for this missense assessment. REVEL is 0.814, which is above the generic BP4 supporting cutoff of <= 0.29 and therefore does not support a benign/no-impact computational conclusion. It is also not in the REVEL gray-zone resolution for BP4. BayesDel is not used because no generic ACMG-strength calibration is established. Therefore BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The reviewed case literature does not show IDH1 c.394C>T in a case where the disease has an alternate molecular basis. PMID:37324278 reports the variant in both an ovarian juvenile granulosa cell tumor and enchondromatosis tissue and shows it was absent from sampled normal tissues, supporting a tumor-restricted somatic event rather than an alternate molecular cause of the reported disease. No other reviewed source documents a separate molecular basis in a case carrying this exact variant.
Variant found in a case with an alternate molecular basis for disease.
No exact-variant ClinVar expert-panel classification of Benign or Likely benign is present. ClinVar's available record contains Pathogenic/Likely pathogenic laboratory assertions, has zero expert-panel submissions, and therefore cannot trigger BP6 under the required generic handling.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is IDH1 p.Arg132Cys. The available evidence establishes this exact amino-acid substitution but does not document a previously established pathogenic variant with a different nucleotide change producing the same p.Arg132Cys substitution. The reported p.Arg132H, p.Arg132L, and p.Arg132Ser substitutions change the amino acid and therefore do not satisfy PS1.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PMID:19935646 documents other missense substitutions at IDH1 residue 132, including p.Arg132His, p.Arg132Leu, and p.Arg132Ser, and demonstrates gain-of-function activity. However, the available evidence does not provide an independently established pathogenic classification for any of those alternate missense variants under the governing generic ACMG/AMP evidence record, so PM5 cannot be applied from the paper alone.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before. ... Caveat: Beware of changes that impact splicing rather than at the amino acid/protein level.
PP1 cannot be assessed. The available evidence contains no documented affected family members, parental or sibling genotypes, phenotype concordance across relatives, or meiosis/segregation data for the exact variant.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The available evidence supports that IDH1 missense substitutions at R132 are a recurrent disease-associated mechanism, but it does not establish the gene-level low rate of benign missense variation required by PP2. The exact-variant gnomAD observations are insufficient to characterize the benign missense rate across IDH1.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The case evidence identifies the variant and reports disease contexts in external publications, but does not provide a defined patient's phenotype or family history for this interpretation that can be judged as highly specific for a disease with a single genetic etiology. The available literature includes heterogeneous somatic IDH1-associated tumors and does not establish the required phenotype-specific clinical presentation for the assessed case.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available evidence. gnomAD v4.1 contains one heterozygous allele (1/1613126 total alleles; homozygotes=0), and gnomAD v3.1 non-cancer genomes contain one allele (1/147204; homozygotes=0), but these records do not establish that the carrier was a healthy adult, the relevant inheritance model, or that full penetrance is expected at an early age. No qualifying homozygous, hemizygous, or otherwise phenotype-annotated healthy-adult observation is provided.
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.
BS4 cannot be assessed. No affected family members with variant testing and no phenotype-matched familial segregation dataset are documented, so lack of segregation cannot be established.
Lack of segregation in affected members of a family.
The available evidence does not provide a gene-level disease-variant spectrum showing that IDH1 disease is caused primarily by truncating variants. Evidence for recurrent R132 missense gain-of-function mutations cannot, by itself, quantify whether truncating variants are the primary known disease mechanism, so BP1 is not applied.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 requires documented allelic configuration: either observation in trans with a pathogenic variant in a fully penetrant dominant gene/disorder or observation in cis with a pathogenic variant in any inheritance pattern. PMID:37324278 documents the target variant in tumor tissue and its absence from the patient's normal tissues and both parents' blood, but reports no second pathogenic variant and provides no cis/trans phase information. The available evidence therefore cannot assess BP2.
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.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_005896.4:c.394C>T in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Cys). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM3 is restricted to recessive disorders and requires the variant to be detected in trans with a pathogenic variant, with phase established through parental or offspring testing. The available evidence concerns a somatic IDH1 p.(R132C) tumor variant and does not establish a recessive IDH1 disorder or a recessive inheritance model; therefore PM3 is not applicable.
For recessive disorders, detected in trans with a pathogenic variant...This requires testing of parents (or offspring) to determine phase.
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_005896.4:c.394C>T in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Cys). 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. No VCEP criteria specification covers PM4 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_005896.4:c.394C>T in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Cys). 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. No VCEP criteria specification covers BP3 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
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_005896.4:c.394C>T in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Cys). 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. No VCEP criteria specification covers BP7 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
Every interpreted variant in IDH1, mapped onto the exon structure of NM_005896.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)1 / 1,179,790 | 8.5e-07 |
This variant is present in gnomAD v4.1 (AF= 6.19914e-07; MAF= 0.00006%, 1/1613126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47608e-07; MAF= 0.00008%, 1/1179790 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
The variant is a missense substitution, p.(Arg132Cys), so the generic PP3/BP4 missense path requires REVEL only; the SpliceAI result is not used for this missense assessment. REVEL is 0.814, meeting the generic PP3 supporting threshold of >= 0.644 but not the moderate threshold of >= 0.773. BayesDel is not used because no generic ACMG-strength calibration is established. Therefore PP3 is met at supporting strength.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). ... Missense variant -> REVEL only. ... PP3 (supporting): >= 0.644 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
The variant is a missense substitution, p.(Arg132Cys), so BP4 must be assessed through the REVEL path only; the SpliceAI result is not used for this missense assessment. REVEL is 0.814, which is above the generic BP4 supporting cutoff of <= 0.29 and therefore does not support a benign/no-impact computational conclusion. It is also not in the REVEL gray-zone resolution for BP4. BayesDel is not used because no generic ACMG-strength calibration is established. Therefore BP4 is not met.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc). ... Missense variant -> REVEL only. ... BP4 (supporting): <= 0.29 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997)
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_005896.4:c.394C>T in IDH1 is a missense substitution predicted to produce NP_005887.2:p.(Arg132Cys). 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. No VCEP criteria specification covers BP7 for IDH1, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts possible splice impact for this variant (max delta score = 0.51). REVEL score = 0.814. BayesDel score = 0.415345.
9 paper records listed. 2 cited in the classification.
Similar to R132H mutant protein, R132C, R132L, and R132S mutations all result in a gain-of-function for NADPH-dependent reduction of αKG (Supplementary Figure 4).
Location Results, subsection ‘Mutant IDH1 directly converts αKG to 2HG’; Supplemental Methods, ‘Cloning, Expression, and Purification of ICDH1 wt and mutants in E coli’
Context Purified recombinant human IDH1 mutant proteins expressed in E. coli were assessed in enzymatic assays measuring NADPH-dependent reduction of αKG.
Somatic point mutations at a key arginine residue (R132) within the active site of the metabolic enzyme isocitrate dehydrogenase 1 (IDH1) confer a novel gain of function in cancer cells, resulting in the production of d-2-hydroxyglutarate (2-HG), an oncometabolite.
Location Introduction; Results, biochemical and cell biology profiling
Context Biochemical enzyme-inhibition assays and cellular profiling, including the HT1080 chondrosarcoma cell line expressing IDH1-R132C.
Mutated IDH allele — no./total no. (%) R132C Dose-escalation phase 21/33 (64) 22/35 (63) 47/78 (60) Dose-expansion phase 55/92 (60) 81/144 (56) 109/180 (61)
Table 1 (Continued), mutated IDH allele section
A c.394C>T (p.Arg132Cys) mutation of the IDH1 gene was detected in both the ovarian JGCTs and enchondromatosis but not detected in the peripheral blood, skin tissue, muscle tissue, and oral mucosa samples of the patient, nor in the peripheral blood of the parents of the patient.
Results, sections 3.2 Genetic test results and 3.3 Experimental results in vitro; Discussion
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 6.19914e-07; MAF= 0.00006%, 1/1613126 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47608e-07; MAF= 0.00008%, 1/1179790 alleles, homozygotes = 0).
This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/251292 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16256 alleles, homozygotes = 0).
Absent from gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory). (ClinVarID = 375891)
SpliceAI predicts possible splice impact for this variant (max delta score = 0.51). REVEL score = 0.814. BayesDel score = 0.415345.
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Oncogenic.
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61615256, n = 1377 times).
This variant lies in a statistically significant hotspot.