About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.176C>A, p.(Thr59Lys)
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. 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: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PS3Moderate
PS3 · moderate
CHEK2 T59K was directly tested in a yeast-based DNA damage response complementation assay (Roeb et al. 2012, PMID:22419737) and demonstrated intermediate functional impairment (score 0.51 on a scale normalized to 1.00 wild-type and 0.00 kinase-dead control). The variant was significantly impaired relative to wild-type but retained partial function. Single publication with direct variant testing in a heterologous system qualifies for moderate-strength PS3.
PM2Supporting
PM2 · supporting
NM_007194.4:c.176C>A is present in gnomAD at extremely low frequency: v2.1 AF=0.00159% (4/251,456 alleles, 0 homozygotes) and v4.1 AF=0.00384% (62/1,613,896 alleles, 0 homozygotes). The grpmax filtering allele frequency is 1.121e-05 in v2.1 and 4.019e-05 in v4.1. All values are well below the 0.1% PM2 threshold. No homozygotes observed.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for CHEK2 Version 1.0 v1.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 moderate, PM2 supporting; combination = 1 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
62 / 1,613,896 alleles
gnomAD v4.1: 62 / 1,613,896 alleles. Recorded AF 3.84164e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59074e-05; MAF= 0.00159%, 4/251456 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.51698e-05; MAF= 0.00352%, 4/113734 alleles, homozygotes = 0); grpmax FAF= 1.121e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
12 reported laboratory submissions
12 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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.
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, with the data and sources behind each one.
27 criteria with recorded statuses: 2 met · 21 not met · 0 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.176C>A (p.Thr59Lys) is a missense variant in exon 2 of CHEK2, located in the N-terminal SQ/TQ regulatory domain.
This variant has been observed in gnomAD at extremely low frequency: v2.1 AF=0.00159% (4/251,456 alleles) and v4.1 AF=0.00384% (62/1,613,896 alleles), meeting PM2 at supporting strength.
T59K was directly tested in a yeast-based DNA damage response complementation assay and demonstrated intermediate functional impairment (score 0.51, normalized to wild-type=1.00 and kinase-dead control=0.00), consistent with partial loss of CHEK2-mediated DNA damage response. This meets PS3 at moderate strength (single publication, direct variant testing in a heterologous functional system).
CHEK2 T59K was originally reported in four Icelandic breast cancer patients and additional individuals with colon, ovarian, and gastric cancers, although at frequencies not significantly different from controls.
In silico predictions are conflicting and do not provide consensus: REVEL score is borderline (0.513), PolyPhen-2 predicts benign (0.30), BayesDel is below damaging threshold (0.410), and SIFT provides no prediction for this residue. SpliceAI predicts no splicing impact (max delta 0.00).
The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel CHEK2 specification (VCEP v1.0) provides no per-criterion rules; generic ACMG/AMP 2015 criteria were applied.
No additional pathogenic or likely pathogenic criteria were met. The variant is classified as a Variant of Uncertain Significance (VUS) based on one moderate criterion (PS3) and one supporting criterion (PM2).
No criteria match.
Met · 2
PS3 ModerateCHEK2 T59K was directly tested in a yeast-based DNA damage response complementation assay (Roeb et al. 2012, PMID:22419737) and demonstrated intermediate functional impairment (score 0.51 on a scale normalized to 1.00 wild-type and 0.00 kinase-dead control). The variant was significantly impaired relative to wild-type but retained partial function. Single publication with direct variant testing in a heterologous system qualifies for moderate-strength PS3. Details ▾Hide ▴
Evidence considered
- Direct variant testing in yeast rad53 complementation assay: T59K showed intermediate DNA damage response (score 0.51)
- significantly different from both wild-type (1.00) and kinase-dead negative control (0.00).
Still missing
- No independent replication in a second functional assay or human cell-based system.
- The CHEK2gether ENIGMA study (PMID:37449874) did not include T59K among its 430 characterized missense variants.
Sources
PM2 SupportingNM_007194.4:c.176C>A is present in gnomAD at extremely low frequency: v2.1 AF=0.00159% (4/251,456 alleles, 0 homozygotes) and v4.1 AF=0.00384% (62/1,613,896 alleles, 0 homozygotes). The grpmax filtering allele frequency is 1.121e-05 in v2.1 and 4.019e-05 in v4.1. All values are well below the 0.1% PM2 threshold. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00159%
- 4/251
- 456 alleles
- grpmax FAF=1.121e-05
- 0 homozygotes.
- gnomAD v4.1: AF=0.00384%
- 62/1
- 613
- 896 alleles
- grpmax FAF=4.019e-05
Still missing
- 62 alleles in gnomAD v4.1 is notable for a variant at this frequency
- the variant may be more common in specific subpopulations than the aggregate AF suggests.
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No evidence that a different nucleotide change at the same position produces the same amino acid change (p.Thr59Lys) with a known pathogenic classification. Details ▾Hide ▴
No further detail was recorded.
PS2 No confirmed de novo observation of NM_007194.4:c.176C>A has been reported in the literature or ClinVar submissions. Details ▾Hide ▴
No further detail was recorded.
PS4 No statistically significant case-control enrichment has been demonstrated for NM_007194.4:c.176C>A. The variant was reported in 4 Icelandic breast cancer patients and additional cancer-affected individuals (PMID:12052256) but has also been observed in control populations and at low frequency in gnomAD (62 alleles in v4.1), precluding application of PS4. Details ▾Hide ▴
Evidence considered
- Observed in 4 breast cancer cases and additional individuals with colon
- ovarian
- and gastric cancers in Icelandic cohort (Ingvarsson et al. 2002). No statistically significant enrichment versus controls.
- Present in gnomAD v4.1 at low frequency with 62 alleles
- indicating population presence.
Still missing
- No adequately powered case-control study specific to this variant.
Sources
PM1 T59K is located in the N-terminal SQ/TQ domain (residues ~19-69) of CHEK2, an unstructured regulatory region containing ATM/ATR phosphorylation motifs. This region is not a well-established critical functional domain with statistically significant clustering of pathogenic missense variants. The residue is not flagged as a significant hotspot by cancerhotspots.org. Neither the FHA domain nor the kinase domain — the two domains with well-characterized pathogenic missense clustering — are affected. Details ▾Hide ▴
Evidence considered
- T59 lies within the SQ/TQ domain
- not the FHA or kinase domains where pathogenic missense variants cluster.
- cancerhotspots.org: residue not significant
- exact variant not listed.
Sources
PM6 No confirmed de novo observation of NM_007194.4:c.176C>A has been reported. Details ▾Hide ▴
No further detail was recorded.
PP1 Familial segregation data reported by Ingvarsson et al. (PMID:12052256) is incomplete and does not support PP1. In one family with colon cancer, a third affected member did not carry T59K. In a second family with breast cancer, two affected individuals did not carry T59K. The absence of complete segregation and co-occurrence of non-carrier affected relatives precludes application of PP1. Details ▾Hide ▴
Evidence considered
- Two families with T59K reported but incomplete segregation: a colon cancer family had one non-carrier affected relative
- a breast cancer family had two non-carrier affected relatives.
- No formal co-segregation analysis or LOD score has been published.
Still missing
- No systematic segregation study with statistical analysis has been performed.
Sources
PP2 PP2 is applicable to genes where missense variants are a predominant disease mechanism and the gene has a low rate of benign missense variation. CHEK2 has both truncating (e.g., c.1100delC) and missense pathogenic variants. The most prevalent pathogenic variant is a frameshift, and the gene does not meet the PP2 requirement for a gene where missense is the primary mechanism. Details ▾Hide ▴
No further detail was recorded.
PP3 In silico predictions are conflicting and do not reach consensus. REVEL score is borderline (0.513), BayesDel is below threshold (0.410), PolyPhen-2 predicts benign (0.30), and SIFT provides no prediction for this residue. SpliceAI delta score is 0.00. Roeb et al. (PMID:22419737) reported an in silico consensus of 'no consensus' (nc) across Align-GVGD, PolyPhen-2, and SIFT. The totality of in silico evidence is inconclusive. Details ▾Hide ▴
Evidence considered
- REVEL: 0.513 (borderline
- just above typical 0.5 threshold).
- BayesDel: 0.410 (below damaging threshold).
- PolyPhen-2: 0.30 (benign).
- SIFT: no prediction available for this residue.
- SpliceAI: max delta 0.00
- no splicing impact predicted.
- Align-GVGD: C65 (highest risk class).
- In silico consensus (per Roeb 2012): no consensus.
Sources
PP4 No evidence that the patient's phenotype or family history is highly specific for CHEK2-related cancer predisposition relative to other hereditary cancer syndromes. The cancers reported in T59K carriers (breast, colon, ovarian, gastric) overlap with multiple hereditary cancer syndromes and are not uniquely specific to CHEK2. Details ▾Hide ▴
Evidence considered
- T59K carriers presented with breast
- colon
- ovarian
- and gastric cancers — phenotypes overlapping with multiple cancer predisposition syndromes.
Sources
PP5 ClinVar variation ID 142041 is classified as Uncertain Significance by 12 clinical laboratories with review status 'criteria provided, single submitter.' There is no expert panel (3-star) classification. Under the global PP5 rule requiring ClinVar 3-star expert panel classification, PP5 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar ID 142041: VUS
- 12 submitters
- review status 'criteria provided
- single submitter' (1-star). No expert panel review.
Sources
BA1 The maximum allele frequency in gnomAD is 0.00508% (NFE, v4.1), well below the 1% BA1 threshold. Details ▾Hide ▴
BS1 The maximum allele frequency in gnomAD is 0.00508% (NFE, v4.1), well below the 0.3% BS1 threshold. Details ▾Hide ▴
BS2 No evidence that T59K has been observed in healthy adults at an age where full penetrance of CHEK2-related cancer predisposition would be expected, with a frequency sufficient to rule out pathogenicity. Details ▾Hide ▴
No further detail was recorded.
BS3 The only published functional assay for T59K (PMID:22419737) demonstrated intermediate functional impairment (score 0.51), not wild-type-like function. This result does not support a benign classification — it indicates partial loss of function. Details ▾Hide ▴
Evidence considered
- Yeast complementation assay: T59K showed significantly reduced DNA damage response (score 0.51) compared to wild-type (1.00)
- indicating partial loss of function
- not normal activity.
Sources
BS4 No evidence of lack of segregation with disease in affected families. The two families reported by Ingvarsson et al. (PMID:12052256) showed incomplete segregation, which is not sufficient to demonstrate non-segregation for BS4 application. Details ▾Hide ▴
Evidence considered
- Incomplete segregation reported in two families — insufficient to meet BS4 threshold for lack of segregation.
Sources
BP1 BP1 applies when a missense variant is found in a gene for which only truncating variants are known to cause disease. CHEK2 has well-established pathogenic missense variants (e.g., p.I157T, p.R117G, p.R145W) and the most common pathogenic variant (c.1100delC) is truncating. The gene does not meet the BP1 criterion of being a gene where only truncating variants cause disease. Details ▾Hide ▴
No further detail was recorded.
BP2 No evidence of NM_007194.4:c.176C>A occurring in trans with a known pathogenic CHEK2 variant has been reported. Details ▾Hide ▴
No further detail was recorded.
BP4 While some in silico tools predict a benign effect (PolyPhen-2: 0.30 benign; SpliceAI: 0.00), other predictors are conflicting or borderline (REVEL: 0.513; Align-GVGD: C65 highest risk). The overall in silico evidence does not convincingly support a benign interpretation. Details ▾Hide ▴
Evidence considered
- PolyPhen-2: 0.30 (benign).
- SpliceAI max delta: 0.00 (no splicing impact).
- However
- REVEL (0.513) and Align-GVGD (C65) suggest potential deleterious effect
- and BayesDel is borderline (0.41). In silico results are not consistently benign.
Sources
BP5 No observation of NM_007194.4:c.176C>A occurring in trans with a known pathogenic CHEK2 variant has been reported. Details ▾Hide ▴
No further detail was recorded.
BP6 No reputable source classifies NM_007194.4:c.176C>A as benign or likely benign. ClinVar classification is VUS with 1-star review status. Under the global BP6 rule requiring ClinVar 3-star expert panel classification, BP6 is not met. Details ▾Hide ▴
Evidence considered
- ClinVar ID 142041: VUS
- no benign classification from any submitter. No expert panel review.
Sources
PS5 No evidence that a different pathogenic variant has been reported at nucleotide position c.176. Details ▾Hide ▴
No further detail was recorded.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice). NM_007194.4:c.176C>A is a missense variant (p.Thr59Lys) and does not meet generic PVS1 null-variant criteria. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo pathogenic missense variant at the same residue (Thr59) was identified. PM5 candidate harvesting returned zero same-residue comparator variants. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 is for in-frame deletions/insertions in repetitive regions. This is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_007194.4:c.176C>A is a missense variant (p.Thr59Lys). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.176C>A
- Protein (HGVS p.)
- NP_009125.1:p.(Thr59Lys)
- GRCh38
- chr22:28734546 G>T
- GRCh37
- chr22:29130534 G>T
- ClinVar
- 142041
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
62 / 1,613,896 alleles
AF 3.84e-05 · 0 homozygotes · FAF 4.02e-05
gnomAD v2.1
4 / 251,456 alleles
AF 1.59e-05 · 0 homozygotes · FAF 1.12e-05
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.8e-05 · 62 / 1,613,896 alleles · 0 hom · FAF 4e-05
| European (non-Finnish)60 / 1,180,020 | 5.1e-05 |
| Remaining individuals2 / 62,486 | 3.2e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.6e-05 · 4 / 251,456 alleles · 0 hom · FAF 1.1e-05
| European (non-Finnish)4 / 113,734 | 3.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.84164e-05; MAF= 0.00384%, 62/1613896 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08466e-05; MAF= 0.00508%, 60/1180020 alleles, homozygotes = 0); grpmax FAF= 4.019e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59074e-05; MAF= 0.00159%, 4/251456 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.51698e-05; MAF= 0.00352%, 4/113734 alleles, homozygotes = 0); grpmax FAF= 1.121e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.513
- BayesDel
- 0.410
How the predictions were used
PP3 In silico predictions are conflicting and do not reach consensus. REVEL score is borderline (0.513), BayesDel is below threshold (0.410), PolyPhen-2 predicts benign (0.30), and SIFT provides no prediction for this residue. SpliceAI delta score is 0.00. Roeb et al. (PMID:22419737) reported an in silico consensus of 'no consensus' (nc) across Align-GVGD, PolyPhen-2, and SIFT. The totality of in silico evidence is inconclusive. Details ▾Hide ▴
Evidence considered
- REVEL: 0.513 (borderline
- just above typical 0.5 threshold).
- BayesDel: 0.410 (below damaging threshold).
- PolyPhen-2: 0.30 (benign).
- SIFT: no prediction available for this residue.
- SpliceAI: max delta 0.00
- no splicing impact predicted.
- Align-GVGD: C65 (highest risk class).
- In silico consensus (per Roeb 2012): no consensus.
Sources
BP4 While some in silico tools predict a benign effect (PolyPhen-2: 0.30 benign; SpliceAI: 0.00), other predictors are conflicting or borderline (REVEL: 0.513; Align-GVGD: C65 highest risk). The overall in silico evidence does not convincingly support a benign interpretation. Details ▾Hide ▴
Evidence considered
- PolyPhen-2: 0.30 (benign).
- SpliceAI max delta: 0.00 (no splicing impact).
- However
- REVEL (0.513) and Align-GVGD (C65) suggest potential deleterious effect
- and BayesDel is borderline (0.41). In silico results are not consistently benign.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_007194.4:c.176C>A is a missense variant (p.Thr59Lys). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.513. BayesDel score = 0.410012.
9 paper records listed. 1 cited in the classification.
Cited in the classification
-
PMID 22419737 ↗Response to DNA damage of CHEK2 missense mutations in familial breast cancer.Roeb W et al. · 2012 Jun 15Roeb et al. developed a yeast-based assay to assess CHEK2-mediated DNA damage response for 25 germline missense variants identified in familial breast cancer patients. T59K (c.176C>A) was directly tested and demonstrated intermediate functional impairment with a quantitative score of 0.51 (normalized to wild-type=1.00 and kinase-dead D347A=0.00). The variant was classified as 'intermediate' — significantly impaired relative to wild-type but retaining partial function above the negative control. In silico predictions were inconclusive: PolyPhen-2 predicted benign (0.30), SIFT had no prediction, Align-GVGD assigned C65 (highest risk class), with an overall in silico consensus of 'no consensus.'→ PS3 Names this variant
Source detail
c.176C>A, T59K, SQ/TQ domain, PolyPhen2: 0.30 Benign, SIFT: no prediction, in silico consensus: nc, Present results: 0.51
Location Table 1 (rows for position 22:29,130,534 G>T, c.176C>A, T59K); Results; Discussion
Context Yeast (S. cerevisiae) rad53/sml1 deletion complementation assay; DNA damage induced by MMS; growth measured as functional readout; 2-4 independent experiments with 6 replicates each
Other recorded publications
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PMID 12052256 ↗Mutation analysis of the CHK2 gene in breast carcinoma and other cancers.Ingvarsson S et al. · 2002Ingvarsson et al. screened breast and other tumors for CHK2 mutations and identified the T59K germline missense variant (c.176C>A, p.Thr59Lys). T59K was found in 4 individuals with breast cancer, 1 with colon and ovarian cancer, 1 with colon cancer, and 1 with gastric cancer among Icelandic patients. Family analysis identified 2 additional carriers. Incomplete segregation was observed: one colon cancer family had a non-carrier affected relative and one breast cancer family had two non-carrier affected relatives. The authors concluded T59K is likely a low-penetrance allele.Names this variant
Quoted passage
A missense mutation at codon 59 was also detected, which substituted lysine for threonine.
Results section (single continuous text); Tables 2, 3, 4
-
PMID 12610780 ↗Variants in CHEK2 other than 1100delC do not make a major contribution to breast cancer susceptibility.Schutte M et al. · 2003Schutte et al. screened CHEK2 coding sequence in familial breast cancer cases and controls. T59K was cited as having been reported in four Icelandic individuals with breast cancer by Ingvarsson et al. (2002). T59K was not among the variants evaluated in their own case-control analysis, which focused on R117G, R145W, and I157T.Names this variant
Quoted passage
T59K, which was reported in four Icelandic individuals with breast cancer (Ingvarsson et al. 2002).
Discussion, paragraph 5
-
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.Richards et al. (2015) published the ACMG/AMP standards and guidelines for sequence variant interpretation. This is a methods guideline paper and does not discuss CHEK2 or NM_007194.4:c.176C>A specifically.Does not name this variant
-
PMID 26206375 ↗GESPA: classifying nsSNPs to predict disease association.Khurana JK et al. · 2015Khurana et al. described GESPA, a computational tool for classifying non-synonymous SNPs to predict disease association. The paper does not specifically discuss CHEK2 T59K or NM_007194.4:c.176C>A.Does not name this variant
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi et al. described a standardized DNA variant scoring system for pathogenicity assessments in Mendelian disorders. The paper does not specifically discuss CHEK2 T59K or NM_007194.4:c.176C>A.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. · 2017Decker et al. sequenced ATM, CHEK2, PALB2, and XRCC2 coding regions in 13,087 breast cancer cases and 5,488 controls. The study focused on rare protein-truncating variants and did not analyze or mention the CHEK2 c.176C>A (T59K) missense variant.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. · 2023Stolarova et al. (ENIGMA CHEK2gether Project) analyzed 430 CHEK2 missense VUS using two parallel functional assays (KAP1 phosphorylation and CHK2 autophosphorylation) and performed case-control association analysis. CHEK2 T59K (c.176C>A) was not among the 430 characterized variants included in this study.Does not name this variant
-
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
62 / 1,613,896 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
12 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 ↗
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/142041/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29130534-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28734546-G-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/22-28734546-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.176C…
- OncoKB ↗www.oncokb.org/gene/CHEK2/T59K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.176C%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= 3.84164e-05; MAF= 0.00384%, 62/1613896 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08466e-05; MAF= 0.00508%, 60/1180020 alleles, homozygotes = 0); grpmax FAF= 4.019e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.59074e-05; MAF= 0.00159%, 4/251456 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.51698e-05; MAF= 0.00352%, 4/113734 alleles, homozygotes = 0); grpmax FAF= 1.121e-05.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (12 clinical laboratories). (ClinVarID = 142041)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.513. BayesDel score = 0.410012.
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.