About SMAD4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMAD4 c.1067C>T, p.(Pro356Leu)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PM1Moderate
PM1 · moderate
Residue Pro356 is located in the SMAD4 MH2 domain (aa 324-552), a well-established critical functional domain that mediates SMAD oligomerization and transcriptional activation. Pathogenic missense variants cluster in the MH2 domain in JP-HHT. This residue additionally lies within a statistically significant hotspot identified by the cancer hotspots pipeline.
PM2Moderate
PM2 · moderate
Variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Allele frequency is 0.0 across all population databases, well below the <0.1% threshold for PM2 under generic ACMG/AMP rules applied to autosomal dominant disorders.
PP3Supporting
PP3 · supporting
Multiple in silico predictors support a deleterious effect: REVEL score 0.968 (well above 0.932 threshold for damaging prediction), BayesDel score 0.541 (above 0.27 threshold). SpliceAI predicts no significant splice impact (max delta score 0.03), but this does not offset the strong missense pathogenicity predictions.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, PP3 supporting; combination = 2 moderate + 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
40 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV61685209, n = 40 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 3 met · 12 not met · 7 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_005359.5:c.1067C>T (p.Pro356Leu) is a missense variant in exon 9 of SMAD4. It is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting rarity in the general population.
Residue Pro356 is located in the SMAD4 MH2 domain (aa 324-552), a well-established critical functional domain that mediates SMAD oligomerization and transcriptional activation. This residue additionally lies within a statistically significant mutational hotspot.
Multiple in silico predictors support a deleterious effect: REVEL score 0.968 (damaging), BayesDel score 0.541 (damaging). SpliceAI predicts no significant splice impact (max delta 0.03).
This variant has been reported in ClinVar as Uncertain Significance by a single clinical laboratory (Ambry Genetics; ClinVar ID 1782219). It has been observed in 40 somatic cancer samples (COSMIC COSV61685209) and is classified as Likely Oncogenic by OncoKB.
PVS1 is not applicable (missense variant). In silico evidence meets PP3 (supporting). Population absence meets PM2 (moderate). MH2 domain location and hotspot status meet PM1 (moderate). Verified criteria: PM1 (moderate) + PM2 (moderate) + PP3 (supporting). Under ACMG/AMP 2015 combination rules, 2 moderate + 1 supporting is insufficient for Likely Pathogenic (requires ≥3 moderate, or 2 moderate + ≥2 supporting). No benign criteria are met. PS3 (functional) and PP1 (segregation) were not assessed because variant-specific evidence could not be verified in accessible full-text publications. Overall classification: Uncertain Significance (VUS).
Gaps: Variant-specific germline functional studies (PS3) and co-segregation data (PP1) were referenced in exploratory literature review (PMID:20101697, PMID:15031030) but could not be verified — abstracts do not mention this variant and full texts are unavailable. Resolution of these gaps could upgrade the classification to Likely Pathogenic.
No criteria match.
Met · 3
PM1 ModerateResidue Pro356 is located in the SMAD4 MH2 domain (aa 324-552), a well-established critical functional domain that mediates SMAD oligomerization and transcriptional activation. Pathogenic missense variants cluster in the MH2 domain in JP-HHT. This residue additionally lies within a statistically significant hotspot identified by the cancer hotspots pipeline. Details ▾Hide ▴
Evidence considered
- SMAD4 MH2 domain (aa 324-552) is critical for protein function.
- Residue 356 lies in a statistically significant hotspot.
- SMAD4 loss of function is an established germline disease mechanism for JPS and JP-HHT.
Sources
pvs1_gene_context
PM2 ModerateVariant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0. Allele frequency is 0.0 across all population databases, well below the <0.1% threshold for PM2 under generic ACMG/AMP rules applied to autosomal dominant disorders. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AC=0).
- gnomAD v4.1: absent (AC=0).
- gnomAD-Canada v1.0: absent (AC=0).
Sources
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score 0.968 (well above 0.932 threshold for damaging prediction), BayesDel score 0.541 (above 0.27 threshold). SpliceAI predicts no significant splice impact (max delta score 0.03), but this does not offset the strong missense pathogenicity predictions. Details ▾Hide ▴
Evidence considered
- REVEL: 0.968 (damaging).
- BayesDel: 0.540787 (moderately damaging).
- SpliceAI max delta: 0.03 (no splice impact).
Sources
Not met · 12 · evaluated, threshold not reached
PS2 No de novo occurrence with confirmed maternity and paternity has been reported for NM_005359.5:c.1067C>T. ClinVar submission SCV002718105 (Ambry Genetics) does not report de novo status. Exploratory literature search identified no de novo reports. Details ▾Hide ▴
Evidence considered
- ClinVar VCV001782219: single clinical testing submission without de novo annotation.
Still missing
- No de novo case with confirmed parentage identified in public databases.
Sources
PS4 ClinVar contains a single submission (Ambry Genetics, SCV002718105) classifying this variant as Uncertain Significance. No multiple independent proband counts or case-control data are available. Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, but this supports rarity (PM2) rather than independently establishing enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 VUS submission
- single submitter.
- gnomAD v2.1: absent.
- gnomAD v4.1: absent.
Still missing
- No case-control odds ratio. No aggregate proband count from published cohorts. Exploratory agent's claim of 'multiple P/LP submissions' in ClinVar is incorrect — only 1 VUS submission exists.
Sources
PM6 No presumed de novo occurrence (without confirmed maternity/paternity) has been reported for this variant. ClinVar submission does not annotate de novo status, and no published case report identifies a de novo observation. Details ▾Hide ▴
Evidence considered
- ClinVar SCV002718105: no de novo annotation.
Still missing
- No de novo observation (confirmed or unconfirmed) found.
Sources
PP5 ClinVar classification is Uncertain Significance (single submitter, Ambry Genetics SCV002718105), not Pathogenic or Likely Pathogenic. No reputable source has classified this variant as pathogenic with evidence unavailable for independent review. The eight ClinVar-associated PMIDs are all general guideline or technical standards papers that do not mention this variant. Details ▾Hide ▴
Evidence considered
- ClinVar VUS (1 submitter).
- ClinVar-associated PMIDs are guidelines/standards
- not variant-specific.
Sources
BA1 Variant is absent from gnomAD v2.1 and v4.1. Allele frequency does not exceed the BA1 threshold of >1% in any population database. Details ▾Hide ▴
BS1 Variant is absent from all population databases. Allele frequency does not exceed the BS1 threshold of >0.3% under generic ACMG/AMP non-VCEP rules. Details ▾Hide ▴
BS2 BS2 requires observation in a healthy adult individual (homozygous for recessive, or hemizygous/heterozygous for fully penetrant dominant) with complete penetrance expected at an early age. No such observation for this variant in a healthy adult has been reported. Variant is absent from gnomAD, which includes ostensibly healthy population controls. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- no healthy carrier identified.
Sources
BS3 No well-established functional studies demonstrate a benign effect of p.Pro356Leu on protein function. OncoKB classifies this variant as Likely Oncogenic (somatic), which contradicts a benign functional interpretation. REVEL score 0.968 and BayesDel 0.541 both predict damaging effects. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Oncogenic (contradicts benign).
- REVEL: 0.968 (damaging).
- BayesDel: 0.541 (damaging).
Still missing
- No benign functional study identified.
Sources
BS4 No evidence of non-segregation with disease in affected family members. BS4 requires that the variant does not segregate with disease, which would contradict pathogenic interpretation. No such observation exists. Details ▾Hide ▴
Still missing
- No non-segregation studies identified.
BP2 BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder. SMAD4-associated disorders are autosomal dominant. No biallelic SMAD4 observations have been reported, as this would likely be lethal. Details ▾Hide ▴
Evidence considered
- SMAD4 is autosomal dominant
- no trans observation reported.
BP4 Multiple in silico predictors support a damaging effect: REVEL 0.968 (damaging) and BayesDel 0.541 (damaging). SpliceAI max delta 0.03 indicates no splice impact, but this does not offset the strong missense pathogenicity predictions. BP4 is contradicted by the preponderance of in silico evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.968 (damaging — contradicts BP4).
- BayesDel: 0.541 (damaging — contradicts BP4).
- SpliceAI: max delta 0.03 (no splice impact — supports BP4 but is outweighed).
Sources
BP6 BP6 requires classification as Benign or Likely Benign by a reputable source without access to the underlying evidence. ClinVar classification is Uncertain Significance (single submitter, Ambry Genetics), not Benign or Likely Benign. Details ▾Hide ▴
Not assessed · 7 · no assessment recorded
PS1 No evidence of a different nucleotide change producing the same amino acid substitution (Pro356Leu) was identified. No comparator variants at the nucleotide level were found in ClinVar or literature for this position. Details ▾Hide ▴
Still missing
- No same-amino-acid-by-different-nucleotide comparator identified.
PS3 OncoKB classifies this variant as Likely Oncogenic based on somatic curated evidence, suggesting functional data exist. Exploratory literature review referenced PMID:20101697 for functional characterization, but the abstract does not mention c.1067C>T or p.Pro356Leu and no full text is available for verification. Without verified variant-specific functional study data, germline PS3 cannot be applied. COSMIC reports 40 somatic occurrences (COSV61685209) but these are somatic, not germline functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Likely Oncogenic (somatic context).
- COSMIC: COSV61685209
- n=40 somatic occurrences.
Still missing
- Variant-specific germline functional studies not verified. Full text of PMID:20101697 unavailable
- abstract does not mention this variant. PMID:25972366 (cited by exploratory agent as SMAD4 review) is actually about ECT for neuropsychiatric lupus — not a SMAD4 reference.
Sources
oncokb ↗20101697
PP1 Exploratory literature review suggested co-segregation of c.1067C>T with JP-HHT in a family (PMID:15031030, Gallione et al. 2004), but the PubMed abstract does not mention this specific variant. No full text is available for verification. Segregation evidence cannot be applied without confirmation that the variant is specifically identified. Details ▾Hide ▴
Still missing
- Putative segregation in PMID:15031030 cannot be verified — abstract does not list specific variants. Full text unavailable.
Sources
15031030
PP2 PP2 applies to genes with a low rate of benign missense variation where missense variants are a common mechanism of disease. SMAD4 has established pathogenic missense variants in the MH2 domain, and loss of function is the disease mechanism. However, formal missense constraint metrics (e.g., gnomAD missense Z-score, missense depletion metrics) were not retrieved for this case, and PP2 is not routinely applied under generic ACMG/AMP without explicit gene-level constraint data. Details ▾Hide ▴
Evidence considered
- SMAD4 LOF mechanism supported for JPS/JP-HHT.
- Pathogenic missense variants documented in MH2 domain.
Still missing
- No formal missense constraint metrics (Z-score
- o/e) retrieved for SMAD4.
Sources
pvs1_gene_context
PP4 No patient-specific phenotypic or family history data were provided for this case. PP4 requires that the patient's phenotype or family history is highly specific for the disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype or family history available.
BP5 BP5 requires identification of the variant in a case with an alternate molecular basis for disease. No such case has been reported or is available for assessment. Details ▾Hide ▴
Still missing
- No case with an alternate molecular basis identified.
PS5 PS5 is an alternative to PM5 when multiple pathogenic variants at the same codon exist but the specific PM5 comparator cannot be confirmed. No comparator variants at codon 356 were identified. PM5 candidate harvesting returned zero candidates. Details ▾Hide ▴
Still missing
- No pathogenic missense comparators at Pro356 identified in ClinVar or literature.
Sources
pm5_candidates
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 applies only to null variants (nonsense, frameshift, canonical splice ±1,2, exon deletion). NM_005359.5:c.1067C>T is a missense variant (p.Pro356Leu) in exon 9; variant_bucket classified as 'other' by generic PVS1 framework. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a null variant.
- pvs1_variant_assessment: apply_generic_pvs1_framework=false
- variant_bucket='other'
Sources
pvs1_gene_contextpvs1_variant_assessment
PM5 N/ANo alternative pathogenic missense variant at Pro356 with a different amino acid change was identified. PM5 candidate harvesting returned zero candidates at this residue in ClinVar. Unable to confirm classic same-residue PM5 semantics. Details ▾Hide ▴
Evidence considered
- pm5_candidates: total_candidates_seen=0
- same_residue_candidates=0.
Sources
pm5_candidates
BP1 N/ABP1 applies only to genes where truncating variants are the sole cause of disease. SMAD4 has established pathogenic missense variants, particularly in the MH2 domain, in JPS and JP-HHT. Details ▾Hide ▴
Evidence considered
- SMAD4 pathogenic missense variants are documented in JP-HHT
- the gene does not have a truncating-only disease mechanism.
Sources
pvs1_gene_context
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_005359.5:c.1067C>T is a missense variant (p.Pro356Leu), not synonymous. SpliceAI max delta score is 0.03, consistent with no splice impact, but the variant class is missense. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
- SpliceAI: max delta 0.03 (no splice impact).
Sources
Identifiers
- Gene
- SMAD4
- Transcript
- NM_005359.5
- Coding (HGVS c.)
- NM_005359.5:c.1067C>T
- Protein (HGVS p.)
- NP_005350.1:p.(Pro356Leu)
- GRCh38
- chr18:51065534 C>T
- GRCh37
- chr18:48591904 C>T
- ClinVar
- 1782219
- COSMIC
- COSV61685209
Gene diagram
Every interpreted variant in SMAD4, mapped onto the exon structure of NM_005359.5. Select a row to find it on the plot.
SMAD4NM_005359.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SMAD4
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.968
- BayesDel
- 0.541
How the predictions were used
PP3 SupportingMultiple in silico predictors support a deleterious effect: REVEL score 0.968 (well above 0.932 threshold for damaging prediction), BayesDel score 0.541 (above 0.27 threshold). SpliceAI predicts no significant splice impact (max delta score 0.03), but this does not offset the strong missense pathogenicity predictions. Details ▾Hide ▴
Evidence considered
- REVEL: 0.968 (damaging).
- BayesDel: 0.540787 (moderately damaging).
- SpliceAI max delta: 0.03 (no splice impact).
Sources
BP4 Multiple in silico predictors support a damaging effect: REVEL 0.968 (damaging) and BayesDel 0.541 (damaging). SpliceAI max delta 0.03 indicates no splice impact, but this does not offset the strong missense pathogenicity predictions. BP4 is contradicted by the preponderance of in silico evidence. Details ▾Hide ▴
Evidence considered
- REVEL: 0.968 (damaging — contradicts BP4).
- BayesDel: 0.541 (damaging — contradicts BP4).
- SpliceAI: max delta 0.03 (no splice impact — supports BP4 but is outweighed).
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_005359.5:c.1067C>T is a missense variant (p.Pro356Leu), not synonymous. SpliceAI max delta score is 0.03, consistent with no splice impact, but the variant class is missense. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
- SpliceAI: max delta 0.03 (no splice impact).
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.968. BayesDel score = 0.540787.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 35101336 ↗Standards for the classification of pathogenicity of somatic variants in cancer (oncogenicity): Joint recommendations of Clinical Genome Resource (ClinGen), Cancer Genomics Consortium (CGC), and Variant Interpretation for Cancer Consortium (VICC).Horak P et al. · 2022Horak et al. (2022) published joint recommendations of ClinGen, CGC, and VICC on standards for classification of oncogenicity of somatic variants in cancer. This is a standards framework paper; NM_005359.5:c.1067C>T was not identified.Does not name this variant
-
PMID 20301299 ↗Heritable Thoracic Aortic Disease Overview.Adam MP et al. · 1993This ClinVar-associated reference lacked an abstract in the publication metadata. NM_005359.5:c.1067C>T was not identified in available information.Does not name this variant
-
PMID 22918138 ↗Opportunities and challenges associated with clinical diagnostic genome sequencing: a report of the Association for Molecular Pathology.Schrijver I et al. · 2012Schrijver et al. (2012) published an Association for Molecular Pathology report on opportunities and challenges of clinical diagnostic genome sequencing. This is a technical report; NM_005359.5:c.1067C>T was not identified.Does not name this variant
-
PMID 24882528 ↗Canadian Cardiovascular Society position statement on the management of thoracic aortic disease.Boodhwani M et al. · 2014Boodhwani et al. (2014) published a Canadian Cardiovascular Society position statement on the management of thoracic aortic disease. This is a clinical guideline; NM_005359.5:c.1067C>T was not identified.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015Hampel et al. (2015) published an ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. This is a clinical practice guideline; NM_005359.5:c.1067C>T was not identified.Does not name this variant
-
PMID 34131312 ↗Chromosomal microarray analysis, including constitutional and neoplastic disease applications, 2021 revision: a technical standard of the American College of Medical Genetics and Genomics (ACMG).Shao L et al. · 2021Shao et al. (2021) published the 2021 revision of ACMG technical standards for chromosomal microarray analysis in constitutional and neoplastic disease. This is a technical guideline; NM_005359.5:c.1067C>T was not identified.Does not name this variant
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PMID 23619274 ↗American College of Medical Genetics and Genomics technical standards and guidelines: microarray analysis for chromosome abnormalities in neoplastic disorders.Cooley LD et al. · 2013Cooley et al. (2013) published ACMG technical standards and guidelines for microarray analysis of chromosome abnormalities in neoplastic disorders. This is a technical guideline; NM_005359.5:c.1067C>T was not identified.Does not name this variant
-
PMID 25173340 ↗2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: Document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC).Erbel R et al. · 2014Erbel et al. (2014) published the 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases. This is a clinical practice guideline; NM_005359.5:c.1067C>T was not identified.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/1782219/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/18-48591904-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr18-51065534-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/18-51065534-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005359.5%3Ac.1067…
- OncoKB ↗www.oncokb.org/gene/SMAD4/P356L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=128485634
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 1782219)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.968. BayesDel score = 0.540787.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV61685209, n = 40 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.