About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.1427C>T, p.(Thr476Met)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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 ClinGen CHEK2 VCEP v1.0.0. 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: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BS1Supporting
BS1 · supporting
The gnomAD v4.1 Middle Eastern subpopulation allele frequency of 0.407% exceeds the BS1 threshold of 0.3% for a dominant disorder. This frequency is higher than expected for a pathogenic CHEK2 variant with moderate penetrance, particularly given the presence of a homozygous carrier in the same subpopulation.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest a benign effect. BayesDel score 0.096 falls within the benign range. SpliceAI max delta score 0.03 predicts no splicing alteration. REVEL score 0.445 is borderline and does not independently predict pathogenicity. Two of three computational tools support a benign interpretation.
Recorded classification: Likely benign
Hereditary Breast, Ovarian and Pancreatic Cancer Specification v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 supporting benign, BP4 supporting benign; combination = 2 supporting benign, which maps to Likely Benign.
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
644 / 1,595,894 alleles
gnomAD v4.1: 644 / 1,595,894 alleles. Recorded AF 0.000403536. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000312997; MAF= 0.03130%, 83/265178 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00127877; MAF= 0.12788%, 9/7038 alleles, homozygotes = 0); grpmax FAF= 0.0004311.
SpliceAI score
0.030 maximum delta
Recorded SpliceAI maximum delta score: 0.030. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
56 reported laboratory submissions
29 Uncertain significance · 22 Likely pathogenic · 1 Likely risk allele · 1 Established risk allele · 1 Pathogenic · 1 Likely Pathogenic · 1 Likely benign.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen CHEK2 VCEP v1.0.0, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 8 not met · 12 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_007194.4:c.1427C>T (p.Thr476Met) is a missense variant in CHEK2 exon 13, located within the protein kinase domain.
This variant is present in gnomAD v2.1 at an allele frequency of 0.0313% (83/265,178 alleles, 0 homozygotes) and in gnomAD v4.1 at 0.0404% (644/1,595,894 alleles) including one homozygous carrier in the Middle Eastern subpopulation (AF 0.407%).
The variant is reported in ClinVar with conflicting classifications: Uncertain significance (29 clinical laboratories), Likely pathogenic (22 laboratories), and single submissions of Pathogenic, Likely benign, Likely risk allele, and Established risk allele (ClinVar Variation ID: 128060).
The Middle Eastern subpopulation allele frequency of 0.407% in gnomAD v4.1 exceeds the BS1 threshold of 0.3%, which is higher than expected for a pathogenic CHEK2 variant (BS1_Supporting).
Multiple in silico tools predict a benign effect: BayesDel score 0.096 is in the benign range and SpliceAI max delta 0.03 predicts no splicing alteration. REVEL score 0.445 is borderline (BP4_Supporting).
The variant was identified as a novel missense substitution in a Bulgarian breast cancer cohort (PMID:22862163, Angelova et al. 2012, n=145 patients), but no case-control statistics or functional characterization were provided.
No well-established functional assay data, segregation studies, or case-control analyses are available to confirm or refute pathogenicity for this specific variant.
The presence of a homozygous carrier in gnomAD v4.1 is notable for an autosomal dominant cancer predisposition gene, though formal BS2 criteria are not met because CHEK2-related cancer risk has incomplete penetrance and adult onset, and the phenotype of the homozygous individual is unknown.
Overall, the available evidence includes one supporting benign criterion (BS1) and one supporting benign criterion (BP4), with no pathogenic criteria met. The evidence favors a benign interpretation but remains insufficient for a definitive classification.
No criteria match.
Met · 2
BS1 SupportingThe gnomAD v4.1 Middle Eastern subpopulation allele frequency of 0.407% exceeds the BS1 threshold of 0.3% for a dominant disorder. This frequency is higher than expected for a pathogenic CHEK2 variant with moderate penetrance, particularly given the presence of a homozygous carrier in the same subpopulation. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 Middle Eastern subpopulation AF 0.407% (18/4
- 424 alleles) exceeds BS1 threshold of 0.3%
- one homozygous carrier observed.
Sources
BP4 SupportingMultiple lines of computational evidence suggest a benign effect. BayesDel score 0.096 falls within the benign range. SpliceAI max delta score 0.03 predicts no splicing alteration. REVEL score 0.445 is borderline and does not independently predict pathogenicity. Two of three computational tools support a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel 0.096 (benign
- below 0.13 threshold)
- SpliceAI max delta 0.03 (no splicing impact)
- REVEL 0.445 (borderline
- below 0.5 pathogenic threshold).
Sources
Not met · 8 · evaluated, threshold not reached
PS4 No case-control study demonstrating statistically significant enrichment of NM_007194.4:c.1427C>T in affected individuals versus controls has been identified. PMID:22862163 reported the variant in Bulgarian breast cancer patients but without case-control comparison or odds ratio. The variant is present in gnomAD population databases at low frequency, precluding a simple absence-based case enrichment argument. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF 0.0313% (83/265
- 178 alleles)
- gnomAD v4.1 AF 0.0404% (644/1
- 595
- 894 alleles)
- PMID:22862163 identified T476M in a Bulgarian breast cancer cohort (n=145) without case-control statistics.
Still missing
- No case-control study quantifying odds ratio for this variant.
Sources
PM1 Although p.Thr476Met is located within the CHEK2 protein kinase domain (residues ~229-507), a critical functional domain, the presence of a homozygous carrier in gnomAD v4.1 (Middle Eastern population) and a subpopulation allele frequency of 0.407% indicate that this residue tolerates variation in the general population. PM1 requires that the domain have low tolerance for benign variation, which is not supported by the population data for this specific residue. Details ▾Hide ▴
Evidence considered
- UniProt O96017: Thr476 lies within the protein kinase domain (residues 229-507)
- gnomAD v4.1: one homozygous carrier in Middle Eastern population
- subpopulation AF 0.407%.
Sources
PM2 While gnomAD v2.1 overall allele frequency (0.0313%) is below the generic PM2 threshold of 0.1%, gnomAD v4.1 data reveal a higher frequency (0.0404% overall; 0.407% in the Middle Eastern subpopulation) including one homozygous carrier. This population presence, particularly the homozygote, does not support absence from population databases as required for PM2. The variant is not sufficiently rare to meet PM2 when considering the larger v4.1 dataset. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 83/265
- 178 alleles (AF 0.0313%)
- 0 homozygotes
- gnomAD v4.1: 644/1
- 595
- 894 alleles (AF 0.0404%)
- 1 homozygote in Middle Eastern population (AF 0.407%).
Sources
PP3 Multiple computational tools do not support a deleterious effect. REVEL score 0.445 is below the commonly used pathogenic threshold of 0.5. BayesDel score 0.096 is in the benign range (threshold <0.13 for benign). SpliceAI max delta score 0.03 predicts no splicing alteration. No HCI prior probability is available for CHEK2. The preponderance of in silico evidence does not support PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.445 (borderline
- below 0.5 threshold)
- BayesDel 0.096 (benign
- below 0.13 threshold)
- SpliceAI max delta 0.03 (no predicted splicing impact)
- HCI prior not available for CHEK2.
Sources
PP5 No reputable source has definitively classified this variant as pathogenic. ClinVar classification is predominantly Uncertain significance with conflicting submissions (29 VUS vs. 22 Likely pathogenic vs. 1 Pathogenic). The lack of consensus and the predominance of VUS classifications do not support PP5. Details ▾Hide ▴
Evidence considered
- ClinVar: 29 labs report Uncertain significance
- 22 report Likely pathogenic
- 1 Pathogenic
- 1 Likely benign
- overall VUS predominance.
Sources
BA1 The highest observed population allele frequency is 0.407% in the gnomAD v4.1 Middle Eastern subpopulation, which does not exceed the 1% threshold required for BA1. The variant is not sufficiently common to be considered a benign polymorphism by allele frequency alone. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 Middle Eastern AF 0.407% (18/4
- 424 alleles)
- below BA1 threshold of 1%.
Sources
BS2 Although one homozygous carrier is present in gnomAD v4.1 (Middle Eastern population), BS2 requires observation in a healthy adult with a disorder expected to have full penetrance at an early age. CHEK2-related cancer predisposition has incomplete penetrance and adult onset, and gnomAD does not provide phenotype data to confirm the homozygous individual is cancer-free. The homozygote finding is suggestive but does not strictly meet the BS2 requirement for this adult-onset, incompletely penetrant condition. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: one homozygous carrier in Middle Eastern subpopulation
- phenotype of this individual is unknown.
Still missing
- Phenotype of the gnomAD homozygous carrier unknown
- BS2 requires confirmation of healthy status in context of full
- early-onset penetrance.
Sources
BP6 No reputable source has definitively classified this variant as benign. One ClinVar submission from Myriad Genetics classifies as Likely benign (SCV004020185), but this is a single flagged submission and does not constitute a reputable consensus. The majority of ClinVar submissions report Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar: single Likely benign submission (Myriad Genetics
- flagged)
- majority classification is Uncertain significance (29 labs).
Sources
Not assessed · 12 · no assessment recorded
PS1 No known pathogenic variant at the same amino acid position (Thr476) with a different nucleotide change has been identified. Without a same-residue pathogenic comparator, PS1 cannot be applied. Details ▾Hide ▴
Still missing
- No same-amino-acid pathogenic comparator available for Thr476.
PS2 No documented de novo occurrence of NM_007194.4:c.1427C>T has been identified in the literature or databases. PS2 requires confirmed de novo status with parental testing. Details ▾Hide ▴
Still missing
- No de novo observation reported for this variant.
Sources
33193653
PS3 No well-established functional assay data demonstrating a damaging effect for p.Thr476Met has been confirmed. PMID:22419737 tested 25 CHEK2 missense variants in a yeast-based DNA damage response assay, but whether p.Thr476Met was among those tested could not be verified from the available abstract or data sources. Details ▾Hide ▴
Evidence considered
- PMID:22419737 abstract describes yeast-based functional assay of 25 CHEK2 missense alleles but does not enumerate which variants were tested.
Still missing
- Variant-specific functional assay data not available
- full text of PMID:22419737 needed to determine whether p.Thr476Met was among the 25 tested alleles.
Sources
2241973722114986
PM6 No assumed de novo occurrence (unconfirmed parentage) has been reported for this variant. PM6 requires observation of a de novo event without confirmation of parental relationships. Details ▾Hide ▴
Still missing
- No assumed de novo data available.
PP1 No cosegregation data have been published for NM_007194.4:c.1427C>T with disease in multiple affected family members. PP1 requires demonstration of variant cosegregation with disease phenotype. Details ▾Hide ▴
Still missing
- No family segregation studies available.
Sources
15095295
PP2 PP2 requires a low rate of benign missense variation in the gene and that missense variants are a common mechanism of disease. CHEK2 missense constraint metrics (e.g., Z-score) were not available in the current data sources to determine whether the gene meets the threshold for PP2 application. Details ▾Hide ▴
Still missing
- CHEK2 missense constraint Z-score not available in data sources
- needed to assess PP2 applicability.
PP4 No patient-specific phenotype 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 gene in question. Details ▾Hide ▴
Still missing
- Patient phenotype and family history data not available.
BS3 No well-established functional assay demonstrating a benign effect for p.Thr476Met has been identified. PMID:22419737 tested 25 CHEK2 missense alleles, some of which exhibited wild-type-like DNA damage response, but whether p.Thr476Met was among those and which functional category it fell into cannot be determined from the available data. Details ▾Hide ▴
Evidence considered
- PMID:22419737 tested 25 CHEK2 missense variants in yeast-based DNA damage response assay
- 5 had WT-like response
- 8 partial loss
- 12 complete loss. Cannot confirm T476M inclusion or category.
Still missing
- Full text of PMID:22419737 needed to determine functional classification of p.Thr476Met.
Sources
2241973722114986
BS4 No segregation data demonstrating lack of cosegregation with disease have been published for this variant. BS4 requires observation that the variant does not segregate with disease in affected families. Details ▾Hide ▴
Still missing
- No segregation data available to assess BS4.
Sources
15095295
BP2 No observation of this variant in trans with a known pathogenic CHEK2 variant (in a recessive model) or in cis with a pathogenic variant (in a dominant model) has been reported. BP2 requires specific phase information. Details ▾Hide ▴
Still missing
- No phased variant co-occurrence data available.
BP5 No evidence is available indicating that this variant was found in a case with an alternate molecular basis for disease. BP5 requires identification of a different causative pathogenic variant in the same individual. Details ▾Hide ▴
Still missing
- No alternate molecular basis data available.
PS5 No reputable source has independently and definitively classified this variant as pathogenic with evidence that can be verified. ClinVar classification is predominantly Uncertain significance with conflicting submissions from multiple laboratories. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance (29 labs)
- Likely pathogenic (22 labs)
- conflicting classifications.
Still missing
- No verified independent pathogenic classification available.
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007194.4:c.1427C>T is a missense variant (p.Thr476Met), not a null variant (nonsense, frameshift, or canonical splice site). PVS1 is not applicable for missense substitutions per ACMG/AMP guidelines. Details ▾Hide ▴
Evidence considered
- Missense substitution at codon 476 (Thr>Met)
- variant falls outside null variant buckets per ClinGen SVI PVS1 framework (PMC6185798).
Sources
pvs1_variant_assessment
PM5 N/ANo alternative missense change at the same amino acid residue (Thr476) classified as pathogenic was identified. The automated PM5 candidate harvest found zero same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue comparators for Thr476.
Sources
pm5_candidates
BP1 N/ACHEK2 disease is caused by both protein-truncating and missense variants. PMID:21244692 demonstrated that rare, evolutionarily unlikely missense substitutions in CHEK2 confer breast cancer risk equivalent to protein-truncating variants. Missense variants are an established disease mechanism in CHEK2, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- PMID:21244692: rare missense substitutions in CHEK2 confer risk approximately equivalent to protein-truncating variants.
Sources
21244692
BP7 N/ANM_007194.4:c.1427C>T is a missense variant (p.Thr476Met), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a synonymous variant
- BP7 does not apply.
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.1427C>T
- Protein (HGVS p.)
- NP_009125.1:p.(Thr476Met)
- GRCh38
- chr22:28694066 G>A
- GRCh37
- chr22:29090054 G>A
- ClinVar
- 4768296, 128060
Gene diagram
Every interpreted variant in CHEK2, mapped onto the exon structure of NM_007194.4. Select a row to find it on the plot.
CHEK2NM_007194.4
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 CHEK2
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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
644 / 1,595,894 alleles
AF 0.000404 · 1 homozygotes · FAF 0.00263
gnomAD v2.1
83 / 265,178 alleles
AF 0.000313 · 0 homozygotes · FAF 0.000431
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 0.0004 · 644 / 1,595,894 alleles · 1 hom · FAF 0.0026
| Middle Eastern18 / 4,424 | 0.00411 hom |
| European (non-Finnish)577 / 1,179,424 | 0.00049 |
| Remaining individuals18 / 62,198 | 0.00029 |
| African/African American15 / 74,930 | 0.0002 |
| Admixed American10 / 59,988 | 0.00017 |
| South Asian6 / 90,970 | 6.6e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00031 · 83 / 265,178 alleles · 0 hom · FAF 0.00043
| Remaining individuals9 / 7,038 | 0.0013 |
| European (non-Finnish)62 / 124,190 | 0.0005 |
| African/African American6 / 23,448 | 0.00026 |
| Admixed American6 / 35,222 | 0.00017 |
0 alternate alleles recorded in 4 other groups: Ashkenazi Jewish, East Asian, European (Finnish), South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000403536; MAF= 0.04035%, 644/1595894 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.00406872; MAF= 0.40687%, 18/4424 alleles, homozygotes = 1); grpmax FAF= 0.00262965.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000312997; MAF= 0.03130%, 83/265178 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00127877; MAF= 0.12788%, 9/7038 alleles, homozygotes = 0); grpmax FAF= 0.0004311.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.445
- BayesDel
- 0.096
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest a benign effect. BayesDel score 0.096 falls within the benign range. SpliceAI max delta score 0.03 predicts no splicing alteration. REVEL score 0.445 is borderline and does not independently predict pathogenicity. Two of three computational tools support a benign interpretation. Details ▾Hide ▴
Evidence considered
- BayesDel 0.096 (benign
- below 0.13 threshold)
- SpliceAI max delta 0.03 (no splicing impact)
- REVEL 0.445 (borderline
- below 0.5 pathogenic threshold).
Sources
PP3 Multiple computational tools do not support a deleterious effect. REVEL score 0.445 is below the commonly used pathogenic threshold of 0.5. BayesDel score 0.096 is in the benign range (threshold <0.13 for benign). SpliceAI max delta score 0.03 predicts no splicing alteration. No HCI prior probability is available for CHEK2. The preponderance of in silico evidence does not support PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.445 (borderline
- below 0.5 threshold)
- BayesDel 0.096 (benign
- below 0.13 threshold)
- SpliceAI max delta 0.03 (no predicted splicing impact)
- HCI prior not available for CHEK2.
Sources
BP7 N/ANM_007194.4:c.1427C>T is a missense variant (p.Thr476Met), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a synonymous variant
- BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.445. BayesDel score = 0.0956883.
10 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 15095295 ↗Limited relevance of the CHEK2 gene in hereditary breast cancer.Dufault MR et al. · 2004No paper-specific finding is recorded.
-
PMID 22114986 ↗CHEK2 contribution to hereditary breast cancer in non-BRCA families.Desrichard A et al. · 2011No paper-specific finding is recorded.
-
PMID 22419737 ↗Response to DNA damage of CHEK2 missense mutations in familial breast cancer.Roeb W et al. · 2012No paper-specific finding is recorded.
-
PMID 23552953 ↗Dissecting the genotype in syndromic intellectual disability using whole exome sequencing in addition to genome-wide copy number analysis.Classen CF et al. · 2013No paper-specific finding is recorded.
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
-
PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
-
PMID 26845104 ↗Improving performance of multigene panels for genomic analysis of cancer predisposition.No paper-specific finding is recorded.
-
PMID 28135145 ↗Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer.No paper-specific finding is recorded.
-
PMID 27621404 ↗Conflicting Interpretation of Genetic Variants and Cancer Risk by Commercial Laboratories as Assessed by the Prospective Registry of Multiplex Testing.No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
644 / 1,595,894 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.030
Open source ↗
ClinVar
29 Uncertain significance · 22 Likely pathogenic · 1 Likely risk allele · 1 Established risk allele · 1 Pathogenic · 1 Likely Pathogenic · 1 Likely benign
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/522546466
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/128060/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29090054-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28694066-G-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.1427…
- OncoKB ↗www.oncokb.org/gene/CHEK2/T476M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.1427C%3ET
- 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
This variant is present in gnomAD v4.1 (AF= 0.000403536; MAF= 0.04035%, 644/1595894 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.00406872; MAF= 0.40687%, 18/4424 alleles, homozygotes = 1); grpmax FAF= 0.00262965.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000312997; MAF= 0.03130%, 83/265178 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00127877; MAF= 0.12788%, 9/7038 alleles, homozygotes = 0); grpmax FAF= 0.0004311.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (29 clinical laboratories) and as Likely pathogenic (22 clinical laboratories) and as Likely risk allele (1 clinical laboratory) and as Established risk allele (1 clinical laboratory) and as Pathogenic (1 clinical laboratory) and as Likely Pathogenic (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 128060)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.445. BayesDel score = 0.0956883.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CHEK2, an intracellular kinase involved in control of the cell cycle, is altered in various cancer types.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.