About CHEK2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CHEK2 c.953G>A, p.(Arg318His)
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
NM_007194.4:c.953G>A is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0046% (13/282,864 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.0045% (73/1,613,934 alleles, 0 homozygotes). Both are below the 0.1% threshold for PM2.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign effect. REVEL score is 0.061 (below pathogenicity threshold), BayesDel score is -0.127872 (negative = benign), and SpliceAI predicts no splice impact (max delta = 0.00). All available in silico tools are concordant in predicting a neutral 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; 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
73 / 1,613,934 alleles
gnomAD v4.1: 73 / 1,613,934 alleles. Recorded AF 4.52311e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.59585e-05; MAF= 0.00460%, 13/282864 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000112867; MAF= 0.01129%, 4/35440 alleles, homozygotes = 0); grpmax FAF= 3.893e-05.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
16 reported laboratory submissions
15 Uncertain significance · 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 · 14 not met · 7 not assessed · 3 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.953G>A (p.Arg318His) is a missense variant in CHEK2 exon 9, located within the kinase domain. The variant has been observed at extremely low frequency in population databases (gnomAD v2.1: 13/282,864 alleles, AF=0.0046%; v4.1: 73/1,613,934 alleles, AF=0.0045%), consistent with PM2 at supporting level.
Computational in silico tools uniformly predict a benign effect: REVEL score 0.061, BayesDel score -0.127872, and SpliceAI max delta 0.00, supporting BP4 at supporting level.
Dong et al. (2003, PMID:12533788) identified this variant in 1 of 94 early-onset prostate cancer cases and 0 of 423 unaffected controls; it was not found in familial prostate cancer cases, and the single observation does not achieve statistical significance for PS4.
ClinVar reports this variant as Uncertain Significance (15 clinical laboratories) and Likely Benign (1 laboratory). No expert panel has classified this variant.
With PM2 (supporting pathogenic) and BP4 (supporting benign) applied, the evidence is balanced. The variant is classified as Variant of Uncertain Significance (VUS). Additional functional data (BS3/PS3) and case-control studies (PS4) are needed to resolve the classification.
No criteria match.
Met · 2
PM2 SupportingNM_007194.4:c.953G>A is present at extremely low frequency in population databases: gnomAD v2.1 AF=0.0046% (13/282,864 alleles, 0 homozygotes) and gnomAD v4.1 AF=0.0045% (73/1,613,934 alleles, 0 homozygotes). Both are below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=4.6e-05 (13/282
- 864)
- v4.1: AF=4.5e-05 (73/1
- 613
- 934)
- grpmax FAF=3.89e-05 (v2.1)
- 5.44e-05 (v4.1).
Sources
BP4 SupportingMultiple lines of computational evidence support a benign effect. REVEL score is 0.061 (below pathogenicity threshold), BayesDel score is -0.127872 (negative = benign), and SpliceAI predicts no splice impact (max delta = 0.00). All available in silico tools are concordant in predicting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.061
- BayesDel: -0.127872
- SpliceAI max delta: 0.00.
Sources
Not met · 14 · evaluated, threshold not reached
PS4 No statistically significant enrichment of NM_007194.4:c.953G>A was observed in affected individuals versus controls. In PMID:12533788 (Dong et al. 2003), the variant was detected in 1/94 early-onset prostate cancer cases and 0/423 unaffected controls, which does not reach statistical significance for this individual variant. Details ▾Hide ▴
Evidence considered
- PMID:12533788: variant observed in 1/94 clinic prostate tumors
- 0/400 sporadic cases
- 0/298 familial cases
- 0/423 controls. No statistically significant case-control enrichment.
Still missing
- No large-scale case-control study specifically evaluating this variant.
Sources
PMID:12533788 ↗12533788
PM1 Although p.Arg318His resides within the CHEK2 kinase domain (a well-established functional domain spanning residues ~220-486), the specific residue is not a recognized mutational hotspot, and the variant has been observed in population databases at low frequency. Cancer Hotspots did not identify this residue as statistically significant. Details ▾Hide ▴
Evidence considered
- Kinase domain location
- Cancer Hotspots: residue not significant
- gnomAD: variant observed in 13+73 alleles across v2.1 and v4.1.
Still missing
- CHEK2 VCEP does not define specific hotspot regions for PM1 (ruleset payload empty).
Sources
PM5 No pathogenic missense variant at the same amino acid residue (Arg318) with a different amino acid substitution was identified. Automated PM5 candidate search returned no results. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: found=false. No pathogenic comparator at Arg318 with a different amino acid change.
Sources
pm5_candidates
PP1 No cosegregation data is available for this variant. In PMID:12533788, the variant was observed in a single early-onset prostate cancer case and was not identified in any of the 149 familial prostate cancer families screened. Details ▾Hide ▴
Evidence considered
- PMID:12533788: variant not found in familial cases (0/298). No segregation analysis possible.
Still missing
- No family studies with this variant.
Sources
PMID:12533788 ↗12533788
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. CHEK2 has a substantial number of missense variants observed in the general population (gnomAD missense Z-score and constraint metrics are not strongly missense-depleted), and truncating variants are the predominant established pathogenic mechanism. Details ▾Hide ▴
Evidence considered
- Multiple CHEK2 missense variants observed in gnomAD
- CHEK2 is not strongly constrained against missense variation.
Sources
PP3 Multiple lines of in silico evidence predict a benign effect: REVEL score 0.061 (below the 0.5 pathogenicity threshold), BayesDel score -0.127872 (negative score indicates benign), and SpliceAI max delta 0.00 (no predicted splice impact). All available computational tools support a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.061 (benign)
- BayesDel: -0.127872 (benign)
- SpliceAI delta: 0.00 (no splice effect).
Sources
PP5 No reputable source has reported NM_007194.4:c.953G>A as pathogenic. ClinVar reports this variant as Uncertain Significance by 15 clinical laboratories and Likely Benign by 1 laboratory (Myriad Genetics). No expert panel or practice guideline classifies this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: 15 VUS
- 1 LB. No P/LP classification from any submitter. No expert panel review.
Sources
BA1 The maximum allele frequency in gnomAD v2.1 is 0.0046% (grpmax FAF 3.89e-05), far below the BA1 threshold of 1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0046%
- v4.1 AF=0.0045%. Both far below BA1 threshold of 1%.
Sources
BS1 The allele frequency in gnomAD is 0.0046% (v2.1) and 0.0045% (v4.1), far below the BS1 threshold of 0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF=0.0046%
- v4.1 AF=0.0045%. Both far below BS1 threshold of 0.3%.
Sources
BS2 While NM_007194.4:c.953G>A is observed in gnomAD (a general population cohort that includes healthy individuals), the frequency is extremely low (AF ~0.0046%) and does not constitute strong evidence for BS2, which requires observation in healthy adults at a frequency inconsistent with full penetrance for a dominant disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 13/282
- 864 alleles
- 0 homozygotes. Frequency too low for BS2.
Sources
BS4 No cosegregation or nonsegregation data are available for NM_007194.4:c.953G>A. The variant was not identified in familial prostate cancer cases in PMID:12533788, precluding segregation analysis. Details ▾Hide ▴
Evidence considered
- PMID:12533788: variant not found in familial cases. No segregation data.
Still missing
- No family studies with this variant.
Sources
PMID:12533788 ↗12533788
BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease. CHEK2 has multiple well-established pathogenic missense variants (e.g., p.Ile157Thr, p.Arg145Trp, p.Ser428Phe) in addition to truncating variants. Missense changes are a recognized disease mechanism in CHEK2, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- CHEK2 has both truncating and missense pathogenic variants. Missense variants are a known disease mechanism.
Sources
PMID:12533788 ↗12533788
BP6 One clinical laboratory (Myriad Genetics, SCV005896018) classified this variant as Likely Benign, but this constitutes a single submitter. BP6 requires a reputable source (e.g., expert panel, practice guideline) reporting the variant as benign with unavailable evidence. No such source exists. Details ▾Hide ▴
Evidence considered
- Myriad Genetics classification: LB (single submitter). No expert panel or guideline classification.
Sources
PS5 No reputable source has reported NM_007194.4:c.953G>A as pathogenic. ClinVar lists this variant as Uncertain Significance (15 clinical laboratories) and Likely Benign (1 clinical laboratory). Details ▾Hide ▴
Evidence considered
- ClinVar: 15 submissions as VUS
- 1 submission as LB. No P/LP classification from any submitter.
Sources
Not assessed · 7 · no assessment recorded
PS2 No de novo occurrence data (with confirmed paternity and maternity) was identified in the reviewed evidence for NM_007194.4:c.953G>A. Details ▾Hide ▴
Still missing
- No de novo data available for this variant.
PS3 Well-established in vitro functional studies demonstrating a damaging effect on CHEK2 protein function were not confirmed in full-text review. Exploratory evidence (PMID:16835864) suggested R318H does not impair kinase activity, but full text was unavailable for verification. Details ▾Hide ▴
Still missing
- PMID:16835864 (Roeb et al. 2006) and PMID:22419737 (Roeb et al. 2012) may contain functional data on CHEK2 p.Arg318His. Full-text review needed to confirm whether functional assays demonstrate damaging or benign effect.
PM6 No de novo occurrence data (assumed or confirmed) was identified for NM_007194.4:c.953G>A. Details ▾Hide ▴
Still missing
- No de novo data available.
PP4 No patient phenotype or family history data specific to the index case carrying NM_007194.4:c.953G>A was provided for review. Details ▾Hide ▴
Still missing
- Patient phenotype and family history data not available for review.
BS3 Well-established functional studies showing no damaging effect on CHEK2 protein function were not confirmed in full-text review. Exploratory evidence (PMID:16835864, Roeb et al. 2006) reported that R318H does not impair CHEK2 kinase activity, but full text was unavailable for independent verification. If confirmed, this would support BS3 at the supporting or moderate level. Details ▾Hide ▴
Still missing
- PMID:16835864 and/or PMID:22419737 full-text review needed to confirm functional impact of R318H on CHEK2 kinase activity.
BP2 No phase data (in cis or in trans with a known pathogenic variant) is available for NM_007194.4:c.953G>A. Details ▾Hide ▴
Still missing
- No phase data available.
BP5 No data was available regarding an alternative molecular basis for disease in a proband carrying NM_007194.4:c.953G>A. Details ▾Hide ▴
Still missing
- No case data with alternate molecular diagnosis available.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_007194.4:c.953G>A is a missense variant (p.Arg318His). PVS1 is restricted to null variants (nonsense, frameshift, canonical ±1,2 splice site, initiation codon, or exon-level deletions). This variant does not fall into any PVS1 bucket under the ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant
- not a null variant. pvs1_variant_assessment.json confirms apply_generic_pvs1_framework=false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PS1 N/APS1 requires the same amino acid change (p.Arg318His) to have been established as pathogenic via a different underlying nucleotide change. No alternative nucleotide substitution causing p.Arg318His is known to be pathogenic. Details ▾Hide ▴
Evidence considered
- No pathogenic variant at the same residue with a different nucleotide change identified.
BP7 N/ANM_007194.4:c.953G>A is a missense variant (p.Arg318His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Identifiers
- Gene
- CHEK2
- Transcript
- NM_007194.4
- Coding (HGVS c.)
- NM_007194.4:c.953G>A
- Protein (HGVS p.)
- NP_009125.1:p.(Arg318His)
- GRCh38
- chr22:28699893 C>T
- GRCh37
- chr22:29095881 C>T
- ClinVar
- 566273, 220179, 133890
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
73 / 1,613,934 alleles
AF 4.52e-05 · 0 homozygotes · FAF 5.44e-05
gnomAD v2.1
13 / 282,864 alleles
AF 4.6e-05 · 0 homozygotes · FAF 3.89e-05
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 4.5e-05 · 73 / 1,613,934 alleles · 0 hom · FAF 5.4e-05
| Admixed American7 / 59,966 | 0.00012 |
| European (non-Finnish)63 / 1,180,000 | 5.3e-05 |
| East Asian1 / 44,886 | 2.2e-05 |
| African/African American1 / 74,898 | 1.3e-05 |
| South Asian1 / 91,076 | 1.1e-05 |
0 alternate alleles recorded in 5 other groups: Remaining individuals, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 4.6e-05 · 13 / 282,864 alleles · 0 hom · FAF 3.9e-05
| Admixed American4 / 35,440 | 0.00011 |
| European (non-Finnish)7 / 129,168 | 5.4e-05 |
| East Asian1 / 19,952 | 5e-05 |
| South Asian1 / 30,614 | 3.3e-05 |
0 alternate alleles recorded in 4 other groups: African/African American, 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= 4.52311e-05; MAF= 0.00452%, 73/1613934 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000116733; MAF= 0.01167%, 7/59966 alleles, homozygotes = 0); grpmax FAF= 5.437e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.59585e-05; MAF= 0.00460%, 13/282864 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000112867; MAF= 0.01129%, 4/35440 alleles, homozygotes = 0); grpmax FAF= 3.893e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.061
- BayesDel
- -0.128
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign effect. REVEL score is 0.061 (below pathogenicity threshold), BayesDel score is -0.127872 (negative = benign), and SpliceAI predicts no splice impact (max delta = 0.00). All available in silico tools are concordant in predicting a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.061
- BayesDel: -0.127872
- SpliceAI max delta: 0.00.
Sources
PP3 Multiple lines of in silico evidence predict a benign effect: REVEL score 0.061 (below the 0.5 pathogenicity threshold), BayesDel score -0.127872 (negative score indicates benign), and SpliceAI max delta 0.00 (no predicted splice impact). All available computational tools support a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.061 (benign)
- BayesDel: -0.127872 (benign)
- SpliceAI delta: 0.00 (no splice effect).
Sources
BP7 N/ANM_007194.4:c.953G>A is a missense variant (p.Arg318His), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.061. BayesDel score = -0.127872.
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 12533788 ↗Mutations in CHEK2 associated with prostate cancer risk.Dong X et al. · 2003No 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 23555315 ↗Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.Haiman CA 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.Richards S et al. · 2015No 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.Shirts BH et al. · 2016No paper-specific finding is recorded.
-
PMID 30303537 ↗Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.Girard E et al. · 2019No paper-specific finding is recorded.
-
PMID 34933735 ↗Exonic sequencing and MLH3 gene expression analysis of breast cancer patients.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
73 / 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
15 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/133890/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/22-29095881-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr22-28699893-C-T?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_007194.4%3Ac.953G…
- OncoKB ↗www.oncokb.org/gene/CHEK2/R318H
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CHEK2+c.953G%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= 4.52311e-05; MAF= 0.00452%, 73/1613934 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000116733; MAF= 0.01167%, 7/59966 alleles, homozygotes = 0); grpmax FAF= 5.437e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.59585e-05; MAF= 0.00460%, 13/282864 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000112867; MAF= 0.01129%, 4/35440 alleles, homozygotes = 0); grpmax FAF= 3.893e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (15 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 133890)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.061. BayesDel score = -0.127872.
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.