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.1 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.2 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 PS4.3 ClinVar reports this variant as Uncertain Significance (15 clinical laboratories) and Likely Benign (1 laboratory). No expert panel has classified this variant.4 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.
CHEK2
Final classification
VUS
CHEK2 c.953G>A · p.Arg318His
CHEK2
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.
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.
Classification rationale
PM2
BP4
VUS
CHEK2 c.953G>A
PM2 + BP4
→
VUS
Gene diagram
· NM_007194.4 · variants mapped to exon structure
CHEK2
NM_007194.4
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
Population frequency
Overall AF
73 / 1,613,934
0.0045%
Highest · Admixed American
0.012%
Homozygotes
0
grpmax FAF
0.0054%
Allele frequency by ancestry — gnomAD v4.1
observed in 5 of 9 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Admixed American | 7 / 59,966 | 0.012% | 0 |
| European (non-Finnish) | 63 / 1,180,000 | 0.0053% | 0 |
| East Asian | 1 / 44,886 | 0.0022% | 0 |
| African/African American | 1 / 74,898 | 0.0013% | 0 |
| South Asian | 1 / 91,076 | 0.0011% | 0 |
| European (Finnish) | 0 / 64,020 | — | — |
| Amish | 0 / 912 | — | — |
| Middle Eastern | 0 / 6,084 | — | — |
| Ashkenazi Jewish | 0 / 29,606 | — | — |
“
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.
Overall AF
13 / 282,864
0.0046%
Highest · Admixed American
0.011%
Homozygotes
0
grpmax FAF
0.0039%
Allele frequency by ancestry — gnomAD v2.1
observed in 4 of 8 groups
| Ancestry | Allele count | Frequency | Homozygotes |
|---|---|---|---|
| Admixed American | 4 / 35,440 | 0.011% | 0 |
| European (non-Finnish) | 7 / 129,168 | 0.0054% | 0 |
| East Asian | 1 / 19,952 | 0.005% | 0 |
| South Asian | 1 / 30,614 | 0.0033% | 0 |
| African/African American | 0 / 24,968 | — | — |
| Ashkenazi Jewish | 0 / 10,370 | — | — |
| European (Finnish) | 0 / 25,124 | — | — |
| Remaining individuals | 0 / 7,228 | — | — |
“
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.
“
This variant is absent from gnomAD-Canada.
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
Unknown Oncogenic Effect
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
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Literature · 22 PMIDs triaged · 8 high-priority
22papers screened
Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.
12533788 ↗
splicing rna
Mutations in CHEK2 associated with prostate cancer risk.
The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of wh
BP7PP3PP5PS4PVS1
22419737 ↗
functional
Response to DNA damage of CHEK2 missense mutations in familial breast cancer.
Comprehensive sequencing of tumor suppressor genes to evaluate inherited predisposition to cancer yields many individually rare missense alleles of unknown functional and clinical consequence. To address this problem for CHEK2 missense alleles, we developed a yeast-based assay to assess in vivo CHEK2-mediated response to DNA damage. Of 25 germline CHEK2 missense alleles detected in familial breast
BS3PP5PS3PS4
23555315 ↗
functional
Genome-wide testing of putative functional exonic variants in relationship with breast and prostate cancer risk in a multiethnic population.
Rare variation in protein coding sequence is poorly captured by GWAS arrays and has been hypothesized to contribute to disease heritability. Using the Illumina HumanExome SNP array, we successfully genotyped 191,032 common and rare non-synonymous, splice site, or nonsense variants in a multiethnic sample of 2,984 breast cancer cases, 4,376 prostate cancer cases, and 7,545 controls. In breast cance
BS3PP5PS3PS4
25741868 ↗
functional
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.
The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic
BS3PP5PS3PS4
26467025 ↗
functional
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
We developed a rules-based scoring system to classify DNA variants into five categories including pathogenic, likely pathogenic, variant of uncertain significance (VUS), likely benign, and benign. Over 16,500 pathogenicity assessments on 11,894 variants from 338 genes were analyzed for pathogenicity based on prediction tools, population frequency, co-occurrence, segregation, and functional studies
BS3PS3PS4
26845104 ↗
splicing rna
Improving performance of multigene panels for genomic analysis of cancer predisposition.
Screening multiple genes for inherited cancer predisposition expands opportunities for cancer prevention; however, reports of variants of uncertain significance (VUS) may limit clinical usefulness. We used an expert-driven approach, exploiting all available information, to evaluate multigene panels for inherited cancer predisposition in a clinical series that included multiple cancer types and com
BP7PP3PP5PS4PVS1
30303537 ↗
functional
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.
Pathogenic variants in BRCA1 and BRCA2 only explain the underlying genetic cause of about 10% of hereditary breast and ovarian cancer families. Because of cost-effectiveness, multigene panel testing is often performed even if the clinical utility of testing most of the genes remains questionable. The purpose of our study was to assess the contribution of rare, deleterious-predicted variants in DNA
BS3PP5PS3PS4
34933735 ↗
splicing rna
Exonic sequencing and MLH3 gene expression analysis of breast cancer patients.
Breast cancer is the most common cancer in women worldwide. Detection of breast cancer susceptibility genes is an important issue. Also, MLH3 is a DNA mismatch repair gene and mutation in this gene is harmful in different cancers. This study aimed to use exome sequencing to uncover previously undetected breast cancer-predisposing variants. Also, we investigated the MLH3 gene expression of breast c
BP7PP3PP5PS4PVS1
28492532 ↗
background review
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
PS3PS4
Sources & reference links