About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.400G>C, p.(Asp134His)
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 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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases. In gnomAD v2.1, it is observed at AF=2.12×10⁻⁵ (6/282,722 alleles, 0 homozygotes) and in gnomAD v4.1 at AF=1.12×10⁻⁵ (18/1,613,968 alleles, 0 homozygotes). The highest subpopulation frequency is 4.01×10⁻⁵ in African/African American. These frequencies are well below the PM2 threshold of 0.1%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple independent in silico predictors are consistent with a benign or neutral effect. REVEL score is 0.37 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.100 (negative, consistent with benign). SpliceAI max delta score is 0.01 (predicts no splicing impact). The concordance of three orthogonal computational tools supports a lack of functional effect.
Recorded classification: Uncertain significance
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: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, 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
18 / 1,613,968 alleles
gnomAD v4.1: 18 / 1,613,968 alleles. Recorded AF 1.11526e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.12223e-05; MAF= 0.00212%, 6/282722 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00577e-05; MAF= 0.00401%, 1/24964 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
11 reported laboratory submissions
10 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
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.
29 criteria with recorded statuses: 2 met · 18 not met · 0 not assessed · 9 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.400G>C (p.Asp134His) in CHEK2 is a rare missense variant observed at extremely low frequency in population databases (gnomAD v2.1 AF=0.00212%, 6/282,722 alleles), meeting PM2 (supporting).
Multiple in silico predictors are consistent with a benign effect: REVEL score 0.37, BayesDel score -0.100, and SpliceAI max delta 0.01 (no predicted splicing impact), meeting BP4 (supporting).
No variant-specific functional evidence, case-control data, segregation data, or de novo reports were identified in the literature. The ENIGMA CHEK2gether functional study (PMID:37449874) assessed 430 CHEK2 missense VUS but did not include this variant.
ClinVar reports this variant as Uncertain significance (10 clinical laboratories) with one Likely benign submission. No expert panel classification is available.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant as either pathogenic or benign. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v2.1, it is observed at AF=2.12×10⁻⁵ (6/282,722 alleles, 0 homozygotes) and in gnomAD v4.1 at AF=1.12×10⁻⁵ (18/1,613,968 alleles, 0 homozygotes). The highest subpopulation frequency is 4.01×10⁻⁵ in African/African American. These frequencies are well below the PM2 threshold of 0.1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.00212% (6/282722)
- v4.1 AF=0.00112% (18/1613968)
- no homozygotes
- grpmax FAF=2.92×10⁻⁶
Sources
BP4 SupportingMultiple independent in silico predictors are consistent with a benign or neutral effect. REVEL score is 0.37 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.100 (negative, consistent with benign). SpliceAI max delta score is 0.01 (predicts no splicing impact). The concordance of three orthogonal computational tools supports a lack of functional effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.37
- BayesDel=-0.100
- SpliceAI=0.01 — all consistent with no deleterious effect
Sources
Not met · 18 · evaluated, threshold not reached
PS1 No known pathogenic variant at the same amino acid position (p.Asp134) with a different nucleotide change was identified in ClinVar or the literature. The PM5 candidate search did not find any same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic comparator identified
Still missing
- If a pathogenic variant at Asp134 is reported in the future
- PS1 should be re-evaluated
Sources
pm5_candidatesclinvar ↗
PS2 No de novo occurrence data for NM_007194.4:c.400G>C was identified in ClinVar, the reviewed literature, or any other source. Details ▾Hide ▴
Evidence considered
- No de novo report identified
Still missing
- De novo testing data not available
Sources
PS3 No variant-specific functional evidence supporting a damaging effect was identified. The ENIGMA CHEK2gether functional study (PMID:37449874) assessed 430 CHEK2 missense VUS but did not include NM_007194.4:c.400G>C (p.Asp134His) in its analysis. Details ▾Hide ▴
Evidence considered
- ENIGMA CHEK2gether study did not include this variant
- OncoKB reports Unknown Oncogenic Effect
Still missing
- No functional assay data available for this specific variant
Sources
PS4 No case-control enrichment data or case series specific to this variant was identified. While this variant has been observed in clinical testing (ClinVar submissions from multiple laboratories), the absence of controlled case-control data precludes application of PS4. Details ▾Hide ▴
Evidence considered
- Variant observed in clinical testing but no case-control enrichment data available
Still missing
- Case-control studies with variant-specific counts would be needed to apply PS4
Sources
PM1 The p.Asp134 residue does not lie in a statistically significant mutational hotspot. Hotspot analysis found no enrichment at this position. The CHEK2 VCEP framework does not provide domain-level PM1 specifications. Details ▾Hide ▴
Evidence considered
- Residue p.Asp134 is not in a statistically significant hotspot
- no VCEP domain specification available
Still missing
- A CHEK2-specific domain-level PM1 framework from the VCEP would clarify applicability
Sources
PM5 No pathogenic missense variant at the same amino acid residue (p.Asp134) with a different amino acid change was identified. Automated PM5 candidate harvesting did not find any eligible same-residue comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- No same-residue comparator with a pathogenic classification identified
Sources
pm5_candidatesclinvar ↗
PP1 No co-segregation data is available for this variant. None of the reviewed publications reported segregation analysis for NM_007194.4:c.400G>C. Details ▾Hide ▴
Evidence considered
- No co-segregation data identified
Still missing
- Family studies with co-segregation data would be needed
Sources
PP2 CHEK2 is a cancer predisposition gene in which both truncating and missense variants are established disease mechanisms. PP2 is intended for genes where missense variants are a common mechanism of disease and benign missense variation is rare, but the CHEK2 VCEP does not provide a specific PP2 specification, and the gene has a substantial burden of rare missense variants of uncertain significance. Details ▾Hide ▴
Evidence considered
- No VCEP PP2 specification for CHEK2
- generic PP2 not clearly met
Still missing
- VCEP-level PP2 specification would clarify applicability
Sources
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.37 (below the pathogenic threshold of 0.5). BayesDel score is -0.100 (negative, consistent with benign). SpliceAI max delta score is 0.01 (predicts no splicing impact). All three independent computational tools agree on a likely benign or neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.37 (neutral/benign)
- BayesDel=-0.100 (benign)
- SpliceAI=0.01 (no splice impact)
Sources
PP4 No specific phenotype data or clinical presentation details for individuals carrying this variant were identified in the reviewed literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
- No variant-specific phenotype data available
Still missing
- Detailed phenotype information for carriers would strengthen assessment
Sources
BA1 The allele frequency is far below the BA1 threshold of 1%. gnomAD v2.1 AF=0.00212% (6/282,722 alleles) and v4.1 AF=0.00112% (18/1,613,968 alleles). Details ▾Hide ▴
BS1 The allele frequency is below the BS1 threshold of 0.3%. gnomAD v2.1 AF=0.00212% (6/282,722 alleles) and v4.1 AF=0.00112% (18/1,613,968 alleles). The highest subpopulation frequency is 0.00401% in African/African American. Details ▾Hide ▴
BS2 No homozygous observations in gnomAD (0 homozygotes in both v2.1 and v4.1). No data on asymptomatic adult heterozygote frequency above expected controls. Details ▾Hide ▴
Evidence considered
- No homozygotes
- no data on asymptomatic carrier frequency
Still missing
- Population-level penetrance data would clarify BS2
Sources
BS3 No variant-specific functional evidence demonstrating a benign effect was identified. The ENIGMA CHEK2gether functional study (PMID:37449874) did not include this variant. OncoKB reports Unknown Oncogenic Effect with no curated functional data. Details ▾Hide ▴
Evidence considered
- No variant-specific functional data available
- variant not assessed in ENIGMA CHEK2gether
Still missing
- Functional assay data for this specific variant would resolve BS3 vs PS3
Sources
BS4 No segregation data is available for this variant. Lack of segregation with disease in affected families cannot be assessed. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- Family segregation studies needed
Sources
BP2 No observation of this variant in trans with a known pathogenic CHEK2 variant was identified. Details ▾Hide ▴
Evidence considered
- No in-trans observations with pathogenic variants
Still missing
- Phase data with known pathogenic CHEK2 variants not available
Sources
BP5 No observation of this variant in a case with an alternative molecular basis for disease was identified in the reviewed data. Details ▾Hide ▴
Evidence considered
- No co-occurrence with alternative molecular cause documented
Still missing
- Case-level molecular data not available
Sources
BP6 No reputable source has classified this variant as benign. ClinVar reports predominantly Uncertain significance (10 clinical laboratories) with one Likely benign submission (Myriad Genetics). No expert panel classification is available. Details ▾Hide ▴
Evidence considered
- ClinVar: 10 VUS vs 1 LB
- no expert panel classification
- review status is 'criteria provided
- single submitter'
Sources
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.400G>C, p.Asp134His). It does not fall into the null-variant classes of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 application. Details ▾Hide ▴
Evidence considered
- Variant classified as missense in exon 3
- not a null variant
Sources
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CHEK2-related cancer predisposition is autosomal dominant. Details ▾Hide ▴
Evidence considered
- CHEK2-related cancer predisposition is autosomal dominant
- PM3 not applicable
Sources
PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants that change protein length. This is a missense substitution that does not alter protein length. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a protein-length-altering change
PM6 N/ANo de novo occurrence data is available for this variant. PM6 cannot be applied without a confirmed de novo report. Details ▾Hide ▴
Evidence considered
- No de novo data available
Still missing
- De novo testing data not available
Sources
PP5 N/ANo reputable source or expert panel has classified this variant as pathogenic. None of the evaluated PP5-candidate publications (PMID:15604628, PMID:18163131, PMID:24432435, PMID:26389210, PMID:35802134) were found to classify or mention this specific variant. Details ▾Hide ▴
Evidence considered
- No expert panel or reputable source classifies this variant as pathogenic
Sources
BP1 N/ACHEK2 disease mechanism includes both truncating and missense pathogenic variants. BP1 is specifically intended for genes in which only truncating variants cause disease and missense variants are not an established mechanism. Details ▾Hide ▴
Evidence considered
- CHEK2 has both truncating and missense pathogenic variants
Sources
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This is a single nucleotide substitution variant. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame indel
BP7 N/AThis is a missense variant (c.400G>C, p.Asp134His). BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
PS5 N/ANo expert panel or reputable source has classified this variant as pathogenic. ClinVar reports Uncertain significance (10 submitters) and Likely benign (1 submitter), with review status 'criteria provided, single submitter'. Details ▾Hide ▴
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.400G>C
- Protein (HGVS p.)
- NP_009125.1:p.(Asp134His)
- GRCh38
- chr22:28725287 C>G
- GRCh37
- chr22:29121275 C>G
- ClinVar
- 128072
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
18 / 1,613,968 alleles
AF 1.12e-05 · 0 homozygotes · FAF 6.15e-06
gnomAD v2.1
6 / 282,722 alleles
AF 2.12e-05 · 0 homozygotes · FAF 2.92e-06
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.1e-05 · 18 / 1,613,968 alleles · 0 hom · FAF 6.2e-06
| South Asian2 / 91,082 | 2.2e-05 |
| Admixed American1 / 59,974 | 1.7e-05 |
| European (Finnish)1 / 64,038 | 1.6e-05 |
| African/African American1 / 74,932 | 1.3e-05 |
| European (non-Finnish)13 / 1,180,000 | 1.1e-05 |
0 alternate alleles recorded in 5 other groups: Remaining individuals, Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 2.1e-05 · 6 / 282,722 alleles · 0 hom · FAF 2.9e-06
| African/African American1 / 24,964 | 4e-05 |
| European (Finnish)1 / 25,120 | 4e-05 |
| South Asian1 / 30,612 | 3.3e-05 |
| European (non-Finnish)3 / 129,046 | 2.3e-05 |
0 alternate alleles recorded in 4 other groups: Admixed American, Ashkenazi Jewish, East Asian, Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.11526e-05; MAF= 0.00112%, 18/1613968 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19582e-05; MAF= 0.00220%, 2/91082 alleles, homozygotes = 0); grpmax FAF= 6.15e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.12223e-05; MAF= 0.00212%, 6/282722 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00577e-05; MAF= 0.00401%, 1/24964 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.370
- BayesDel
- -0.100
How the predictions were used
BP4 SupportingMultiple independent in silico predictors are consistent with a benign or neutral effect. REVEL score is 0.37 (below the typical pathogenic threshold of 0.5). BayesDel score is -0.100 (negative, consistent with benign). SpliceAI max delta score is 0.01 (predicts no splicing impact). The concordance of three orthogonal computational tools supports a lack of functional effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.37
- BayesDel=-0.100
- SpliceAI=0.01 — all consistent with no deleterious effect
Sources
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.37 (below the pathogenic threshold of 0.5). BayesDel score is -0.100 (negative, consistent with benign). SpliceAI max delta score is 0.01 (predicts no splicing impact). All three independent computational tools agree on a likely benign or neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.37 (neutral/benign)
- BayesDel=-0.100 (benign)
- SpliceAI=0.01 (no splice impact)
Sources
BP7 N/AThis is a missense variant (c.400G>C, p.Asp134His). BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.37. BayesDel score = -0.100278.
9 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 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.ACMG/AMP standards and guidelines for the interpretation of sequence variants. This foundational framework document does not discuss any specific CHEK2 variants.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Describes a rules-based DNA variant scoring system for Mendelian disorders. Does not discuss CHEK2 or any specific variant within CHEK2.Does not name this variant
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PMID 28779002 ↗Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.Decker B et al. · 2017Case-control study assessing rare protein-truncating variants in ATM, CHEK2, and PALB2 for breast cancer risk. Focused exclusively on truncating variants; NM_007194.4:c.400G>C (missense) was not within scope or reported.Does not name this variant
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PMID 30730459 ↗Detection of Pathogenic Germline Variants Among Patients With Advanced Colorectal Cancer Undergoing Tumor Genomic Profiling for Precision Medicine.You YN et al. · 2019Retrospective study of germline pathogenic variants detected incidentally through tumor genomic profiling in advanced colorectal cancer patients. Does not mention NM_007194.4:c.400G>C or any specific CHEK2 missense variants.Does not name this variant
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PMID 30851065 ↗Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system.Delimitsou A et al. · 2019Functional characterization of CHEK2 variants using a Saccharomyces cerevisiae (yeast) system. The abstract does not list NM_007194.4:c.400G>C among the variants studied.Does not name this variant
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PMID 34326862 ↗Analysis of Sequence and Copy Number Variants in Canadian Patient Cohort With Familial Cancer Syndromes Using a Unique Next Generation Sequencing Based Approach.Bhai P et al. · 2021Analysis of sequence and copy number variants in a Canadian patient cohort with familial cancer syndromes using NGS-based multi-gene panels. NM_007194.4:c.400G>C was not specifically reported in this study.Does not name this variant
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PMID 37449874 ↗ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.Stolarova L et al. · 2023ENIGMA CHEK2gether project functionally characterized 430 CHEK2 missense VUS using two parallel assays (KAP1 phosphorylation and CHEK2 autophosphorylation) and subsequent case-control analysis. NM_007194.4:c.400G>C (p.Asp134His) was not among the 430 variants assessed.Does not name this variant
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004Genetic cancer risk assessment and counseling practice recommendations from the National Society of Genetic Counselors (2004). A general guidance document that does not discuss any specific gene variants. CHEK2 is mentioned only in a table listing Li-Fraumeni syndrome-associated genes.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Sherloc refinement of ACMG-AMP variant classification criteria. A methodology paper that does not discuss specific CHEK2 variants or NM_007194.4:c.400G>C.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
18 / 1,613,968 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
10 Uncertain significance · 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/128072/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29121275-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28725287-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/22-28725287-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.400G…
- OncoKB ↗www.oncokb.org/gene/CHEK2/D134H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.400G%3EC
- 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= 1.11526e-05; MAF= 0.00112%, 18/1613968 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 2.19582e-05; MAF= 0.00220%, 2/91082 alleles, homozygotes = 0); grpmax FAF= 6.15e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 2.12223e-05; MAF= 0.00212%, 6/282722 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 4.00577e-05; MAF= 0.00401%, 1/24964 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 128072)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.37. BayesDel score = -0.100278.
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.