rs199708878
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_007194.4(CHEK2):c.7C>T(p.Arg3Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,612,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3L) has been classified as Uncertain significance.
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.7C>T | p.Arg3Trp | missense_variant | 2/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.7C>T | p.Arg3Trp | missense_variant | 2/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000139 AC: 21AN: 151442Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000278 AC: 68AN: 244816Hom.: 1 AF XY: 0.000249 AC XY: 33AN XY: 132754
GnomAD4 exome AF: 0.000135 AC: 198AN: 1461358Hom.: 0 Cov.: 33 AF XY: 0.000154 AC XY: 112AN XY: 726934
GnomAD4 genome ? AF: 0.000139 AC: 21AN: 151560Hom.: 0 Cov.: 31 AF XY: 0.000176 AC XY: 13AN XY: 73998
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:2Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 15, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 20, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 09, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 16, 2021 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Jan 24, 2023 | - - |
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 02, 2022 | Variant summary: CHEK2 c.7C>T (p.Arg3Trp) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00028 in 251936 control chromosomes, predominantly at a frequency of 0.00036 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.15 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.7C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer as well as LFS, prostate cancer, and diffuse large B cell lymphoma without strong evidence for causality/neutral outcome (example, Lee_2001, Laitman_2007, Bell_2007, Tischowitz_2008, deMiranda_2013, Tung_2014, Rummel_2017, Kleiblova_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Multiple publications reporting experimental evidence evaluating an impact on protein function indicate that the variant demonstrated kinase activity and growth in yeast comparable to wild-type (Lee_2001, Kleiblova_2019, Delimitsou_2019), while an additional study showed the variant to have a mildly reduced response to DNA damage (Roeb_2012). Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, one of whom reports a likely benign outcome. Based on the evidence outlined above, the variant was classified as likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 08, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect: most show no or minimal impact on DNA damage response/kinase activity (Lee et al., 2001; Bell et al., 2007; Roeb et al., 2012; Delimitsou et al., 2019; Kleiblova et al., 2019); Observed in individuals with CHEK2-related and other cancers, but also observed in unaffected controls (Lee et al., 2001; Bell et al., 2007; Laitman et al., 2007; Tischkowitz et al., 2008; Rummel et al., 2017); This variant is associated with the following publications: (PMID: 17721994, 22419737, 14569133, 19338683, 23960188, 12610780, 27273131, 31398194, 16080966, 11719428, 18085035, 18571837, 28211887, 28503720, 28873162, 25186627, 24482476, 26296696, 28553140, 30851065, 31050813) - |
Breast and/or ovarian cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 18, 2020 | - - |
CHEK2-related cancer predisposition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Arg3Trp variant was identified in 7 of 6118 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer, prostate cancer, Li-Fraumeni Syndrome or diffuse large B-cell lymphomas and was identified in 2 of 7128 control chromosomes from healthy individuals (Bell 2007, Laitman 2007, Lee 2001, Miranda 2013, Rummel 2017, Schutte 2003, Tischkowitz 2008). The variant was also identified in dbSNP (ID: rs199708878 as "With Uncertain significance allele"), ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics, and Integrated Genetics/Laboratory Corporation of America), and the Zhejiang University Database (4x). The variant was not identified in MutDB database. The variant was identified in control databases in 71 of 270350 chromosomes (1 homozygous) at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6344 chromosomes (freq: 0.0003), Latino in 1 of 34306 chromosomes (freq: 0.00003), European in 7 of 120922 chromosomes (freq: 0.0001), Ashkenazi Jewish in 48 of 9970 chromosomes (freq: 0.01), East Asian in 2 of 18812 chromosomes (freq: 0.0001), and South Asian in 11 of 30678 chromosomes (freq: 0.0004), while the variant was not observed in the African, and Finnish populations. The p.Arg3 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. The variant showed intermediate DNA damage response in CHEK2-mediated DNA damage response assay (Roeb 2012). However, the variant did not show LOH in a primary tumor specimen and demonstrated kinase activity and protein half-life comparable with that of the wild-type protein; the primary tumor assayed was also found to have a homozygous somatic variant in TP53 (Lee 2001). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at