About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.542G>A, p.(Arg181His)
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: 3
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 3
BS3Supporting
BS3 · supporting
BS3 is met at supporting level. Kleiblova et al. (PMID:31050813) performed a well-established cell-based functional assay quantifying CHK2-specific phosphorylation of endogenous KAP1 in human non-transformed RPE1-CHEK2-knock-out cells. The c.542G>A (p.Arg181His) variant was classified as NEUTRAL, retaining >50% of wild-type CHK2 kinase activity. This assay is considered well-validated — it reflects in vivo CHK2 behavior more accurately than in vitro kinase assays, resolves discrepancies seen in prior yeast-based and overexpression systems, and correctly stratified known pathogenic and benign controls. The neutral functional classification provides supporting evidence for a benign effect.
BP4Supporting
BP4 · supporting
BP4 is met at supporting level. Multiple lines of in silico evidence suggest no impact on gene product: SpliceAI predicts no splicing alteration (max delta = 0.00); BayesDel score is -0.032 (benign range, below zero); REVEL score is 0.46, which is borderline and does not reach the typical pathogenic threshold (~0.7). The convergence of SpliceAI and BayesDel on a benign prediction, with REVEL being non-contributory, satisfies BP4 at the supporting level.
BP6Supporting
BP6 · supporting
BP6 is met at supporting level. The ClinVar aggregate classification for Variation ID 5598 is Likely benign, reported by 10 clinical diagnostic laboratories (9 as Likely benign, 1 as Benign). An additional 8 submissions classify it as Uncertain significance and 1 as likely benign. The plurality of clinical laboratories with assertion criteria favor a benign interpretation. No expert panel review has been performed.
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: BS3 supporting, BP4 supporting, BP6 supporting; combination = 3 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
85 / 1,613,934 alleles
gnomAD v4.1: 85 / 1,613,934 alleles. Recorded AF 5.26663e-05. Recorded homozygote count 1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000127304; MAF= 0.01273%, 36/282788 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00125326; MAF= 0.12533%, 25/19948 alleles, homozygotes = 1); grpmax FAF= 0.00089902.
No listed criterion applied
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
19 reported laboratory submissions
9 Likely benign · 8 Uncertain significance · 1 likely benign · 1 Benign.
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.
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: 3 met · 18 not met · 0 not assessed · 5 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.542G>A (p.Arg181His) in CHEK2 is present in gnomAD at low frequency (v2.1 AF=0.0127%, v4.1 AF=0.0053%) with one homozygote observed in the East Asian population.
In a well-established cell-based functional assay (KAP1 phosphorylation in RPE1-CHEK2-KO cells), p.Arg181His was classified as NEUTRAL, retaining >50% of wild-type CHK2 kinase activity (Kleiblova et al. 2019).
Multiple lines of in silico evidence suggest no damaging impact: SpliceAI predicts no splicing alteration (max delta=0.00), BayesDel score is in the benign range (-0.032), and REVEL is borderline (0.46).
ClinVar aggregate classification is Likely benign from 10 clinical diagnostic laboratories, with an additional 8 labs reporting Uncertain significance (Variation ID 5598).
The variant has been reported in 1/400 sporadic prostate cancer cases (Dong et al. 2003), 1/516 familial breast cancer patients (Dufault et al. 2004), and 2/1928 breast/ovarian cancer patients (Kleiblova et al. 2019) without statistically significant enrichment versus controls.
No de novo observations, co-segregation data, or statistically significant case-control enrichment have been reported for this variant.
No criteria match.
Met · 3
BS3 SupportingBS3 is met at supporting level. Kleiblova et al. (PMID:31050813) performed a well-established cell-based functional assay quantifying CHK2-specific phosphorylation of endogenous KAP1 in human non-transformed RPE1-CHEK2-knock-out cells. The c.542G>A (p.Arg181His) variant was classified as NEUTRAL, retaining >50% of wild-type CHK2 kinase activity. This assay is considered well-validated — it reflects in vivo CHK2 behavior more accurately than in vitro kinase assays, resolves discrepancies seen in prior yeast-based and overexpression systems, and correctly stratified known pathogenic and benign controls. The neutral functional classification provides supporting evidence for a benign effect. Details ▾Hide ▴
Evidence considered
- Kleiblova et al. (2019) KAP1 phosphorylation assay in RPE1-CHEK2-KO cells: p.Arg181His classified as NEUTRAL (>50% WT activity).
Sources
PMID:31050813 ↗31050813
BP4 SupportingBP4 is met at supporting level. Multiple lines of in silico evidence suggest no impact on gene product: SpliceAI predicts no splicing alteration (max delta = 0.00); BayesDel score is -0.032 (benign range, below zero); REVEL score is 0.46, which is borderline and does not reach the typical pathogenic threshold (~0.7). The convergence of SpliceAI and BayesDel on a benign prediction, with REVEL being non-contributory, satisfies BP4 at the supporting level. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00 (no splicing impact)
- BayesDel -0.032 (benign)
- REVEL 0.46 (borderline/non-contributory).
Sources
BP6 SupportingBP6 is met at supporting level. The ClinVar aggregate classification for Variation ID 5598 is Likely benign, reported by 10 clinical diagnostic laboratories (9 as Likely benign, 1 as Benign). An additional 8 submissions classify it as Uncertain significance and 1 as likely benign. The plurality of clinical laboratories with assertion criteria favor a benign interpretation. No expert panel review has been performed. Details ▾Hide ▴
Evidence considered
- ClinVar aggregate: 10 of 19 clinical labs with criteria classify as Likely benign/Benign (Variation ID 5598).
Still missing
- No ClinGen expert panel review has been performed for this variant.
Sources
Not met · 18 · evaluated, threshold not reached
PS1 No different nucleotide change at codon 181 producing the same missense change (p.Arg181His) has been established as pathogenic. There is no evidence that c.542G>C or c.542G>T (also producing p.Arg181His) has been classified as pathogenic. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change at codon 181 has been reported or classified as pathogenic.
Still missing
- No established pathogenic variant at this residue from a different nucleotide change.
PS2 No de novo observations have been reported for this variant in public databases or the literature. PS2 requires a confirmed de novo occurrence with both maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar
- literature
- or exploratory search.
Still missing
- No de novo observations available for this variant.
PS3 PS3 requires well-established functional studies showing a damaging effect. In Kleiblova et al. (PMID:31050813), a validated cell-based functional assay (KAP1 phosphorylation in RPE1-CHEK2-KO cells) classified c.542G>A (p.Arg181His) as NEUTRAL, with CHK2 kinase activity retained at >50% of wild-type. This contradicts a damaging interpretation. An exploratory search referenced Boonen et al. (2022, PMID:35654782) as showing a loss-of-function effect, but this source was not verified with full-text and remains unconfirmed. Details ▾Hide ▴
Evidence considered
- Kleiblova et al. (2019) cell-based functional assay classified p.Arg181His as NEUTRAL. Unverified reference to Boonen et al. (2022) suggesting a damaging effect could not be confirmed from available full-text.
Still missing
- Boonen et al. (2022
- PMID:35654782) was referenced by exploratory search as showing a damaging effect for p.R181H
- but full-text verification is needed. Contradictory functional data requires reconciliation.
Sources
PMID:31050813 ↗31050813
PS4 PS4 requires statistically significant enrichment of the variant in affected individuals versus controls. Dong et al. (PMID:12533788) found c.542G>A in 1/400 sporadic prostate cancer cases and 0/423 controls. Dufault et al. (PMID:15095295) found it in 1/516 familial breast cancer patients and 0/500 controls (p=0.38, not significant). Kleiblova et al. (PMID:31050813) found it in 2/1928 patients and 0/3360 population-matched controls. None reached statistical significance. Insufficient proband counts for PS4. Details ▾Hide ▴
Evidence considered
- 3/2844 total patients vs 0/4283 controls across three studies
- no statistically significant enrichment.
Still missing
- No large-scale case-control study with sufficient power to test association for this rare variant.
Sources
PM1 PM1 requires location in a mutational hot spot or critical functional domain with absent or very low benign variation. While codon 181 lies within the FHA domain (important for CHK2 dimerization and activation), functional studies demonstrate that missense variants at this position (p.Arg181His, p.Arg181Cys) are tolerated (classified as NEUTRAL by Kleiblova et al. 2019). The CHEK2 VCEP criteria.json contains no structured PM1 domain specification. Given functional neutrality, PM1 is not supported. Details ▾Hide ▴
Evidence considered
- FHA domain contains codon 181
- but missense variants at this position are functionally neutral per Kleiblova et al. (2019). No VCEP-defined PM1 domain specification available.
Still missing
- CHEK2 VCEP specification (version 1.0.0) has no structured PM1 criteria
- domain boundaries not formally defined in criteria.json.
Sources
PMID:31050813 ↗31050813
PM2 PM2 applies when a variant is absent from population databases. This variant is present in gnomAD: v2.1 AF=0.0001273 (36/282788 alleles, 1 homozygote), v4.1 AF=5.27×10⁻⁵ (85/1613934 alleles, 1 homozygote). While the overall frequency is low (<0.1%), the variant is not absent. The presence of a homozygote in the East Asian population (v2.1, v4.1) indicates the variant is tolerated in a healthy adult, further weakening any PM2 argument. Details ▾Hide ▴
Evidence considered
- Variant present in gnomAD v2.1 (36 alleles
- 1 homozygote) and v4.1 (85 alleles
- 1 homozygote). Homozygote observed in East Asian population.
Sources
PM6 PM6 requires a de novo observation with maternity and paternity confirmed. No de novo reports have been identified for this variant. Details ▾Hide ▴
Evidence considered
- No de novo observations reported in available sources.
Still missing
- No de novo observations.
PP1 PP1 requires co-segregation of the variant with disease in multiple affected family members. No co-segregation data are available for this variant in the literature. Details ▾Hide ▴
Evidence considered
- No published pedigree or co-segregation data for families carrying c.542G>A.
Still missing
- No co-segregation data available.
PP2 PP2 requires a missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease. CHEK2 has a high rate of benign missense variation, exemplified by the common p.I157T variant observed at ~3% population frequency with no significant cancer risk elevation. PP2 is not applicable. Details ▾Hide ▴
Evidence considered
- CHEK2 has a high rate of benign/low-risk missense variation (e.g.
- p.I157T at ~3% frequency with OR <1.5).
Sources
PP3 PP3 requires multiple lines of in silico evidence supporting a deleterious effect. REVEL score is 0.46 (borderline, below typical pathogenic threshold of ~0.7). BayesDel score is -0.032 (benign range). SpliceAI max delta is 0.00 (no splicing impact). HCI prior is not available. The in silico evidence is mixed and does not converge on a damaging prediction. PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.46 (borderline)
- BayesDel -0.032 (benign)
- SpliceAI 0.00 (no impact). In silico evidence does not support a deleterious effect.
Sources
PP4 PP4 requires the patient's phenotype or family history to be highly specific for the gene. No individual-level phenotype data are available for carriers of this variant beyond aggregate counts in case series. Details ▾Hide ▴
Evidence considered
- No patient-specific phenotype data available to assess gene-specificity.
Still missing
- No individual-level phenotype or family history data for carriers.
PP5 PP5 requires a reputable source to have classified the variant as pathogenic. ClinVar aggregate classification for Variation ID 5598 is Likely benign (9 labs), Uncertain significance (8 labs), with 1 additional likely benign and 1 benign. No reputable source has classified this variant as pathogenic; the predominant clinical consensus is benign/likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar aggregate: 10 Likely benign/Benign vs 8 Uncertain significance. No pathogenic classification from reputable sources.
Sources
BA1 BA1 requires allele frequency >1% in a population database. The highest observed population frequency is 0.125% in East Asian (gnomAD v2.1), well below the 1% threshold. Overall AF is 0.0127% (v2.1) and 0.0053% (v4.1). BA1 is not met. Details ▾Hide ▴
Evidence considered
- Maximum population AF 0.125% (EAS v2.1)
- far below 1% threshold.
Sources
BS1 BS1 requires allele frequency >0.3% in a population database. The highest observed population frequency is 0.125% in East Asian (gnomAD v2.1), below the 0.3% threshold. BS1 is not met. Details ▾Hide ▴
Evidence considered
- Maximum population AF 0.125% (EAS v2.1)
- below 0.3% threshold.
Sources
BS2 BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. CHEK2-related cancer predisposition is an autosomal dominant condition with moderate penetrance and adult onset; it does not exhibit full penetrance at an early age. While the variant is observed in gnomAD (including 1 homozygote), the BS2 criterion is not satisfied under the standard ACMG/AMP interpretation due to incomplete penetrance and late onset of CHEK2-associated cancers. Details ▾Hide ▴
Evidence considered
- Variant present in gnomAD with 1 homozygote
- but CHEK2-related cancer is moderate penetrance
- adult-onset — not meeting BS2's requirement of full early-age penetrance.
Sources
BS4 BS4 requires lack of segregation of the variant with disease in affected family members. No segregation studies are available for this variant. Dufault et al. (PMID:15095295) reported the variant in 1/516 familial breast cancer patients and 0/500 controls (p=0.38), but this is case-control frequency data, not segregation analysis. BS4 is not met. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No co-segregation or lack-of-segregation data for families with this variant.
Sources
15095295
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such case has been reported for this variant. Kleiblova et al. (PMID:31050813) noted that carriers in their cohort included one with a coincident BRCA1 mutation, but this was a single observation and the classification as BP5 would require systematic exclusion of CHEK2 contribution. Details ▾Hide ▴
Evidence considered
- No systematic evidence of alternate molecular diagnosis in carriers of this variant.
Still missing
- No report of this variant in a patient with a confirmed alternate genetic etiology.
PS5 PS5 requires a different pathogenic variant at the same amino acid position. The only alternate missense at codon 181 is c.541C>T (p.Arg181Cys). This variant has not been established as pathogenic — it is classified as VUS/neutral in functional studies (Kleiblova et al. 2019 classified it as NEUTRAL; Wu et al. 2006 showed only partially reduced kinase activity). Details ▾Hide ▴
Evidence considered
- p.Arg181Cys (c.541C>T) at the same codon is not established pathogenic
- classified as neutral in functional assays.
Still missing
- No established pathogenic variant at codon 181.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 does not apply to missense variants. NM_007194.4:c.542G>A is a missense substitution (p.Arg181His), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). Generic PVS1 framework (PMC6185798) confirms variant bucket is 'other' with no canonical splice consensus disruption. Details ▾Hide ▴
Evidence considered
- Missense variant
- not eligible for PVS1 per ClinGen SVI PVS1 decision tree (PMC6185798).
Sources
PM5 N/ANo same-residue comparator variants with pathogenic classification were identified. PM5 candidate harvesting returned no valid comparators. Details ▾Hide ▴
Evidence considered
- pm5_candidates.json returned 0 candidates
- unable to confirm same-residue PM5 semantics.
BP1 N/ABP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. CHEK2 has known pathogenic missense variants (e.g., p.Arg117Gly, p.Arg145Trp, p.Gly167Arg in the FHA domain; p.Thr367Metfs in kinase domain from c.1100delC is truncating but missense variants in the kinase domain are also pathogenic). BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- CHEK2 has established pathogenic missense variants
- BP1 is not applicable.
BP2 N/ABP2 applies when a variant is observed in trans with a pathogenic variant for a recessive disorder, or in cis with a pathogenic variant in any inheritance pattern. CHEK2 is an autosomal dominant cancer predisposition gene; BP2 observation in trans with a recessive disorder is not the relevant disease mechanism. Not applicable. Details ▾Hide ▴
Evidence considered
- CHEK2-related cancer predisposition is autosomal dominant
- BP2 observation in trans for a recessive disorder is not applicable.
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_007194.4:c.542G>A is a missense variant (p.Arg181His), not synonymous. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 only applies to synonymous variants.
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.542G>A
- Protein (HGVS p.)
- NP_009125.1:p.(Arg181His)
- GRCh38
- chr22:28725027 C>T
- GRCh37
- chr22:29121015 C>T
- ClinVar
- 5598
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
85 / 1,613,934 alleles
AF 5.27e-05 · 1 homozygotes · FAF 0.000653
gnomAD v2.1
36 / 282,788 alleles
AF 0.000127 · 1 homozygotes · FAF 0.000899
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 5.3e-05 · 85 / 1,613,934 alleles · 1 hom · FAF 0.00065
| East Asian39 / 44,852 | 0.000871 hom |
| South Asian12 / 91,072 | 0.00013 |
| African/African American7 / 75,008 | 9.3e-05 |
| Admixed American4 / 59,984 | 6.7e-05 |
| Remaining individuals3 / 62,504 | 4.8e-05 |
| European (non-Finnish)20 / 1,179,918 | 1.7e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00013 · 36 / 282,788 alleles · 1 hom · FAF 0.0009
| East Asian25 / 19,948 | 0.00131 hom |
| South Asian4 / 30,612 | 0.00013 |
| African/African American2 / 24,960 | 8e-05 |
| European (non-Finnish)4 / 129,118 | 3.1e-05 |
| Admixed American1 / 35,436 | 2.8e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, European (Finnish), Remaining individuals.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.26663e-05; MAF= 0.00527%, 85/1613934 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.000869526; MAF= 0.08695%, 39/44852 alleles, homozygotes = 1); grpmax FAF= 0.00065305.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000127304; MAF= 0.01273%, 36/282788 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00125326; MAF= 0.12533%, 25/19948 alleles, homozygotes = 1); grpmax FAF= 0.00089902.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.460
- BayesDel
- -0.032
How the predictions were used
BP4 SupportingBP4 is met at supporting level. Multiple lines of in silico evidence suggest no impact on gene product: SpliceAI predicts no splicing alteration (max delta = 0.00); BayesDel score is -0.032 (benign range, below zero); REVEL score is 0.46, which is borderline and does not reach the typical pathogenic threshold (~0.7). The convergence of SpliceAI and BayesDel on a benign prediction, with REVEL being non-contributory, satisfies BP4 at the supporting level. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.00 (no splicing impact)
- BayesDel -0.032 (benign)
- REVEL 0.46 (borderline/non-contributory).
Sources
PP3 PP3 requires multiple lines of in silico evidence supporting a deleterious effect. REVEL score is 0.46 (borderline, below typical pathogenic threshold of ~0.7). BayesDel score is -0.032 (benign range). SpliceAI max delta is 0.00 (no splicing impact). HCI prior is not available. The in silico evidence is mixed and does not converge on a damaging prediction. PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL 0.46 (borderline)
- BayesDel -0.032 (benign)
- SpliceAI 0.00 (no impact). In silico evidence does not support a deleterious effect.
Sources
BP7 N/ABP7 applies only to synonymous (silent) variants with no predicted splice impact and low nucleotide conservation. NM_007194.4:c.542G>A is a missense variant (p.Arg181His), not synonymous. BP7 is not applicable. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 only applies to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.46. BayesDel score = -0.0318827.
7 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
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PMID 22419737 ↗Response to DNA damage of CHEK2 missense mutations in familial breast cancer.No paper-specific finding is recorded.
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PMID 31050813 ↗Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer.No paper-specific finding is recorded.
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PMID 12533788 ↗Mutations in CHEK2 associated with prostate cancer risk.No paper-specific finding is recorded.
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PMID 15095295 ↗Limited relevance of the CHEK2 gene in hereditary breast cancer.Dufault MR et al. · 2004No paper-specific finding is recorded.
-
PMID 16835864 ↗Characterization of CHEK2 mutations in prostate cancer.Wu X et al. · 2006No paper-specific finding is recorded.
-
PMID 16982735 ↗Rare germ line CHEK2 variants identified in breast cancer families encode proteins that show impaired activation.Sodha N et al. · 2006No paper-specific finding is recorded.
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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
85 / 1,613,934 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
9 Likely benign · 8 Uncertain significance · 1 likely benign · 1 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/5598/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29121015-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28725027-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.542G…
- OncoKB ↗www.oncokb.org/gene/CHEK2/R181H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.542G%3EA
- 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= 5.26663e-05; MAF= 0.00527%, 85/1613934 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.000869526; MAF= 0.08695%, 39/44852 alleles, homozygotes = 1); grpmax FAF= 0.00065305.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000127304; MAF= 0.01273%, 36/282788 alleles, homozygotes = 1) and has highest observed frequency in the East Asian population (AF= 0.00125326; MAF= 0.12533%, 25/19948 alleles, homozygotes = 1); grpmax FAF= 0.00089902.
ClinVar
This variant has been reported in ClinVar as Likely benign (9 clinical laboratories) and as Uncertain significance (8 clinical laboratories) and as likely benign (1 clinical laboratory) and as Benign (1 clinical laboratory). (ClinVarID = 5598)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.46. BayesDel score = -0.0318827.
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.