The CBL NM_005188.4:c.1111T>C (NP_005179.2:p.(Tyr371His)) missense variant has previously been reported in somatic cancers (COSMIC; COSV50629681, n = 35 times). Experimental evidence: Three independent studies of p.Tyr371His demonstrated cytokine-independent growth and constitutive ERK, AKT, S6, JAK2, LYN, or STAT5 signaling. Based on available guidelines, this variant is considered to be Pathogenic.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A 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.CBL encodes a protein that helps attach ubiquitin to activated signaling proteins, marking them for breakdown and helping limit signals from receptors such as EGFR, PDGFR, MET, and FLT3. Germline changes in CBL are associated with Noonan syndrome and an increased predisposition to juvenile myelomonocytic leukemia. CBL is involved in cancer development, with alterations reported in blood cancers, lung adenocarcinoma, and melanoma.
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, strong: three independent studies of p.Tyr371His demonstrated cytokine-independent growth and constitutive ERK, AKT, S6, JAK2, LYN, or STAT5 signaling.
Met at supporting: gnomAD v4.1 total AF is 2.50e-06 and grpmax FAF is 2.8e-07, both below the PM2 threshold of 0.0001.
Met: one affected child had the variant absent from both tested parents, with de novo origin reported but maternity and paternity confirmation not documented.
Met, strong: REVEL 0.972 exceeds the generic PP3 strong threshold of 0.932 for this missense variant.
No benign criterion marked as applied in the recorded assessment.
Pathogenic: PS3 strong and PP3 strong satisfy the generic two-strong pathogenic-criteria rule, with additional PM6 moderate and PM2 supporting evidence.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 4 / 1,602,246 alleles. Recorded AF 2.4965e-06. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.06247e-05; MAF= 0.00106%, 3/282362 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.01253e-05; MAF= 0.00501%, 1/19950 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.972. Refer to the recorded PP3/BP4 rationale for interpretation.
17 Pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant has previously been reported in somatic cancers (COSMIC; COSV50629681, n = 35 times).
This variant does not lie 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 · 7 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The exact CBL c.1111T>C (p.Tyr371His) variant is reported de novo in one affected child and absent from both tested parents, supporting PM6.
PS2 is not met because the report does not document confirmed maternity and paternity.
No informative affected-relative segregation or non-segregation data are available for PP1 or BS4.
No VCEP covers CBL in this case; generic ACMG/AMP rules govern.
The reviewed literature provides affected-case observations but no exact-variant case-control comparison, while the current case phenotype and complete molecular workup are not supplied.
ClinVar has zero expert-panel submissions for the exact variant; ordinary laboratory submissions and aggregate classifications were not used to trigger PP5 or BP6.
No criteria match.
PS3 is met at strong strength. Three independent functional studies evaluated the exact CBL p.Tyr371His variant. Fernandes et al. (PMID:20622007) showed ligand-independent growth or ligand hyperresponsiveness with FLT3 or KIT, activation of Akt and STAT5, elevated reactive oxygen species, and suppression of transforming activity by hexokinase inhibition. Niemeyer et al. (PMID:20694012) showed cytokine-independent growth and constitutive ERK, AKT, and S6 phosphorylation, specifically in hematopoietic cells with reduced normal CBL expression, providing a disease-relevant genetic control. Javadi et al. (PMID:23696637) showed enhanced survival without GM-CSF, increased GM-CSF receptor beta-chain phosphorylation, elevated JAK2 and LYN expression, increased CBL and S6 phosphorylation, and normalization or inhibition of mutant-associated signaling with JAK2 or SRC-pathway inhibitors. The studies use disease-relevant hematopoietic systems, wild-type or normal-CBL comparisons, pathway readouts, and pharmacologic rescue/inhibition; the convergent results support a damaging gain-of-function effect on CBL. No evidence supports BS3.
PS3: Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
PM2 is met at supporting strength. The variant is present at an extremely low frequency in gnomAD v4.1 all-comers: 4/1602246 alleles, total AF=2.496495544379577e-06, with no homozygotes; the grpmax FAF is 2.8e-07. This is below the supplied generic PM2 threshold of <=0.0001. gnomAD v2.1 also reports only 3/282362 alleles and no homozygotes. The generic default source applies because no governing VCEP specifies a non-cancer or exome-only population subset.
Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
PMID:28414188 reports the exact CBL c.1111T>C (p.Tyr371His) variant as de novo in an affected child, with trio sequencing and Sanger confirmation showing absence in both healthy parents. Because the report does not document confirmed maternity and paternity, this supports assumed de novo evidence under PM6 rather than PS2.
Assumed de novo, but without confirmation of paternity and maternity.
The variant is a missense change, NM_005188.4:c.1111T>C (p.Tyr371His), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3. REVEL is 0.972, meeting the supplied generic PP3 strong threshold of >= 0.932 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... PP3 (strong): >= 0.932 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
PMID:28414188 reports the exact CBL c.1111T>C (p.Tyr371His) variant as de novo in one affected child, with trio whole-exome sequencing and Sanger confirmation showing absence in healthy parents and siblings. However, the supplied report does not document confirmed maternity and paternity or an equivalent parent-identity check. Therefore the evidence does not satisfy the full PS2 requirement, despite supporting a de novo origin.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
The governing rule requires a reputable source to report the variant as pathogenic while the evidence is unavailable to the laboratory for independent evaluation. ClinVar variation 13811 is an exact-variant match, but it has zero expert-panel submissions; its Pathogenic and Likely pathogenic assertions are ordinary laboratory submissions and cannot trigger PP5 under the specified generic rule. In addition, the relevant published evidence is available for independent evaluation. PP5 is not met.
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. The applicable all-comers gnomAD v4.1 data report grpmax FAF=2.8e-07, far below the generic stand-alone threshold of >=0.05. The highest observed population point estimate is East Asian AF=2.229853275654462e-05 from 1/44846 alleles, but the filtering allele frequency is the required metric and is below the threshold. The variant's pathogenic ClinVar consensus also argues against ending classification with a default BA1 call.
Allele frequency is above 5% in Exome Sequencing Project, 1000 Genomes or Exome Aggregation Consortium.
BS1 is not met. The applicable all-comers gnomAD v4.1 grpmax FAF is 2.8e-07, well below the generic default threshold of >=0.01 for an allele frequency greater than expected for the disorder. The highest observed East Asian point estimate, 2.229853275654462e-05 from 1/44846 alleles, cannot replace grpmax FAF. Because the filtering frequency is not elevated, a maximum-credible-frequency calculation is not needed to reject BS1.
Allele frequency is greater than expected for disorder.
BS3 is not met. The reviewed functional studies do not show no damaging effect on CBL function or splicing; instead, all three exact-variant studies report abnormal growth or signaling consistent with a damaging effect. No well-established benign functional or splicing assay for CBL p.Tyr371His was identified.
BS3: Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
The variant is a missense change, so the governing generic rule selects the REVEL path only; SpliceAI cannot be substituted for a gray-zone or non-supportive REVEL result. REVEL is 0.972, which does not meet the strongest BP4 supporting threshold of <= 0.29, and therefore BP4 is not met. The SpliceAI max delta of 0.001 is not counted for BP4 in this missense situation.
BP4: 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) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The governing rule requires a reputable source to report the variant as benign while the evidence is unavailable to the laboratory for independent evaluation. ClinVar variation 13811 has zero expert-panel submissions and contains Pathogenic or Likely pathogenic laboratory assertions, with no exact-variant benign or likely benign expert-panel classification. Ordinary laboratory submissions, aggregate labels, and non-expert assertions cannot trigger BP6 under the specified generic rule. BP6 is not met.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is NP_005179.2:p.(Tyr371His), but the available evidence documents only the same c.1111T>C allele. No previously established pathogenic alternate nucleotide change producing p.Tyr371His was identified, so the same-amino-acid-change requirement cannot be confirmed without treating the variant's own reports as PS1 evidence.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
The governing ACMG/AMP rule requires that the prevalence in affected individuals be significantly increased compared with controls; its numeric guidance is RR or OR >5.0 with a confidence interval that does not include 1.0. The literature_pass packet's PS4 candidate, PMID:20543203, was checked against its available abstract: it reports an affected JMML cohort and CBL mutation observations, but no unaffected control count or matched-ancestry control frequency for the exact c.1111T>C (p.Tyr371His) variant. The reported affected-case count alone cannot provide an OR/RR or 95% CI, so the required inequality cannot be written with an observed estimate: OR/RR > 5.0? not assessable. PS4 is therefore not assessed, not inferred from case observations alone.
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.
The case has no VCEP specification or domain table for CBL. The available evidence describes p.Tyr371His in the CBL linker region and reports functional effects for the variant, but it does not establish a generic ACMG critical functional domain at residue 371 together with the required absence of benign variation. The cancer-hotspot search was negative, and COSMIC occurrence alone is not a generic PM1 route.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
The available PM5 candidate file contains zero same-residue candidates and no pathogenic alternate missense change at Tyr371. The exact p.Tyr371His reports cannot serve as the required different missense change at the same residue.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
The available evidence describes a single affected proband with a de novo variant and unaffected parents and siblings. It does not provide affected relatives carrying the variant, a pedigree with multiple affected family members, or meiosis/segregation data sufficient to evaluate PP1.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.
The case documents a rare CBL missense variant and reports CBL disease-associated missense observations, but it provides no gene-wide benign-missense-rate analysis and no sufficiently complete gene-level variant-spectrum evidence to establish both PP2 requirements.
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 governing rule requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available evidence describes phenotypes in published CBL cases, including the PMID:28414188 case, but does not provide the current case patient's phenotype or family history. Published phenotype observations from another patient cannot establish PP4 for this case, so PP4 is not assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 cannot be assessed from the available population data. gnomAD v4.1 reports four total alleles and no homozygotes, but it does not establish that a carrier was a healthy adult, nor does the case evidence document the required early-age full penetrance of the relevant disorder. The paper extract reports the variant as de novo and absent in unaffected relatives, which is not an observation of the variant in a healthy adult.
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.
The available report identifies unaffected parents and siblings who lack the variant, but it does not describe affected family members who were tested and found not to carry the variant. Thus, it does not establish lack of segregation among affected relatives for BS4.
Lack of segregation in affected members of a family.
The available evidence does not provide a comprehensive CBL disease-variant spectrum showing that disease is caused primarily by truncating variants. A single reported pathogenic missense variant and the presence of germline missense disease reports do not by themselves quantify the gene's predominant pathogenic variant class.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed from the available evidence. The exact variant is reported as a de novo heterozygous CBL variant, but no additional pathogenic variant in the same individual is documented, and no cis or trans phase relationship is reported. The available evidence also does not establish that the relevant dominant CBL disorder is fully penetrant, which is required for the trans pathway of 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.
The governing rule requires the variant to be found in a case with an alternate molecular basis for disease. The available exact-variant case report documents the CBL variant and phenotype but does not establish that the current case, or the reported index patient, has a second pathogenic molecular diagnosis. Absence of that information is insufficient to conclude that no alternate basis exists, so BP5 is not assessed.
Variant found in a case with an alternate molecular basis for disease.
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_005188.4:c.1111T>C in CBL is a missense substitution predicted to produce NP_005179.2:p.(Tyr371His). 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 CBL, 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 not applicable because the available disease context describes the CBL germline disorder as dominant, whereas PM3 is restricted to recessive disorders. The case does not provide a recessive inheritance context or a pathogenic variant demonstrated in trans; the reported c.1111T>C (p.Tyr371His) observation was instead de novo and heterozygous, with the variant absent in the unaffected parents and siblings.
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_005188.4:c.1111T>C in CBL is a missense substitution predicted to produce NP_005179.2:p.(Tyr371His). 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 CBL, 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_005188.4:c.1111T>C in CBL is a missense substitution predicted to produce NP_005179.2:p.(Tyr371His). 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 CBL, 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_005188.4:c.1111T>C in CBL is a missense substitution predicted to produce NP_005179.2:p.(Tyr371His). 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 CBL, 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 CBL, mapped onto the exon structure of NM_005188.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| East Asian1 / 44,846 | 2.2e-05 |
| African/African American1 / 74,698 | 1.3e-05 |
| European (non-Finnish)2 / 1,169,266 | 1.7e-06 |
| East Asian1 / 19,950 | 5e-05 |
| African/African American1 / 24,958 | 4e-05 |
| European (non-Finnish)1 / 128,770 | 7.8e-06 |
This variant is present in gnomAD v4.1 (AF= 2.4965e-06; MAF= 0.00025%, 4/1602246 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22985e-05; MAF= 0.00223%, 1/44846 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 1.06247e-05; MAF= 0.00106%, 3/282362 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.01253e-05; MAF= 0.00501%, 1/19950 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
The variant is a missense change, NM_005188.4:c.1111T>C (p.Tyr371His), so the governing generic rule selects the REVEL path only; SpliceAI and BayesDel are not used for PP3. REVEL is 0.972, meeting the supplied generic PP3 strong threshold of >= 0.932 from the ClinGen SVI REVEL calibration (Pejaver et al. 2022, PMID:36413997).
PP3: Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.) ... PP3 (strong): >= 0.932 — ClinGen SVI REVEL calibration (Pejaver et al. 2022, Am J Hum Genet) (PMID:36413997) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
The variant is a missense change, so the governing generic rule selects the REVEL path only; SpliceAI cannot be substituted for a gray-zone or non-supportive REVEL result. REVEL is 0.972, which does not meet the strongest BP4 supporting threshold of <= 0.29, and therefore BP4 is not met. The SpliceAI max delta of 0.001 is not counted for BP4 in this missense situation.
BP4: 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) ... Missense variant -> REVEL only. Its SpliceAI score says nothing about whether the amino-acid substitution is tolerated, so 'no predicted splice impact' is never BP4 support for a missense variant.
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_005188.4:c.1111T>C in CBL is a missense substitution predicted to produce NP_005179.2:p.(Tyr371His). 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 CBL, 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 no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.972. BayesDel score = 0.543613.
8 paper records listed. 4 cited in the classification.
Characterization of these two CBL mutants revealed that coexpression with the receptor tyrosine kinases FLT3 (Fms-like tyrosine kinase 3) or KIT-induced ligand independent growth or ligand hyperresponsiveness, respectively. Growth of cells expressing mutant CBL required expression and kinase activity of FLT3. In addition to the CBL-dependent phosphorylation of FLT3 and CBL itself, transformation was associated with activation of Akt and STAT5 and required functional expression of the small GTPases Rho, Rac, and Cdc42.
Location Abstract
Context CBL mutant cellular functional characterization in receptor-tyrosine-kinase signaling and AML-relevant growth and survival pathways.
Consistent with these genetic data, the common p.371Y>H altered Cbl protein induces cytokine-independent growth and constitutive phosphorylation of ERK, AKT and S6 only in hematopoietic cells in which normal Cbl expression is reduced by RNA interference.
Location Abstract
Context Disease-relevant hematopoietic-cell assay with RNA-interference reduction of normal CBL expression and growth/signaling readouts.
Expression of CBL mutants in the TF-1 cell line resulted in enhanced survival in the absence of GM-CSF. Cells expressing CBL mutations displayed increased phosphorylation of GM-CSF receptor βc subunit in response to stimulation, although expression of total GM-CSFR βc was lower. This suggested enhanced kinase activity downstream of GM-CSFR.
Location Abstract
Context TF-1 hematopoietic-cell assay examining GM-CSF-dependent survival, receptor and downstream kinase phosphorylation, and inhibitor response.
Figure 2. Family pedigree with Sanger sequencing confirming the de novo CBL missense variant (c.1111T>C) in the index. Variant is absent in healthy, unaffected parents and siblings.
Location Clinical Report, lines 104–115; Figure 2 legend, lines 231–242; Table 1
Context Trio whole-exome sequencing with 44× coverage, Sanger confirmation in the index patient and family members, and population comparison with ExAC, dbSNP, NHLBI ESP, and an in-house database.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls.
ACMG/AMP 2015 criterion definitions
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= 2.4965e-06; MAF= 0.00025%, 4/1602246 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 2.22985e-05; MAF= 0.00223%, 1/44846 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
This variant is present in gnomAD v2.1 (AF= 1.06247e-05; MAF= 0.00106%, 3/282362 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 5.01253e-05; MAF= 0.00501%, 1/19950 alleles, homozygotes = 0).
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (17 clinical laboratories) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 13811)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.972. BayesDel score = 0.543613.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50629681, n = 35 times).
This variant does not lie in a statistically significant hotspot.