chr22-28699893-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate
The NM_007194.4(CHEK2):c.953G>A(p.Arg318His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,934 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R318C) 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 -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.953G>A | p.Arg318His | missense_variant | 9/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.953G>A | p.Arg318His | missense_variant | 9/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152084Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000477 AC: 12AN: 251482Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135914
GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461850Hom.: 0 Cov.: 30 AF XY: 0.0000413 AC XY: 30AN XY: 727220
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152084Hom.: 0 Cov.: 31 AF XY: 0.0000269 AC XY: 2AN XY: 74294
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 22, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 20, 2024 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 318 of the CHEK2 protein (p.Arg318His). This variant is present in population databases (rs143611747, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer (PMID: 22419737, 26845104, 28580595, 34933735, 35264596). This variant is also known as Arg361His. ClinVar contains an entry for this variant (Variation ID: 133890). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 22419737). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | May 06, 2019 | The c.953G>A variant has been reported in individuals with familial breast cancer (Roeb 2012, Shirts 2016). The c.953G>A variant has an overall allele frequency of 0.00004 in the Broad Institute ExAC Browser (http://exac.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 07, 2023 | This missense variant replaces arginine with histidine at codon 318 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit an intermediate functional deficit in a DNA damage repair assay in yeast (PMID: 22419737). This variant has been reported in individuals affected with familial breast cancer (PMID 22419737, 26845104, 28580595), but has also been found in healthy cohorts (PMID 24728327, 30303537, https://whi.color.com/variant/22-29095881-C-T). In a large international case-control study, this variant was reported in 13/60466 breast cancer cases and 5/53461 controls (OR=2.299, 95%CI 0.82 to 6.449, p-value=0.155; PMID: 33471991). This variant has been identified in 13/282864 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 05, 2023 | The p.R318H variant (also known as c.953G>A), located in coding exon 8 of the CHEK2 gene, results from a G to A substitution at nucleotide position 953. The arginine at codon 318 is replaced by histidine, an amino acid with highly similar properties. This variant was detected in an individual diagnosed with early-onset prostate cancer (<59 years of age); authors note that this finding is likely a germline mutation, but could represent an early somatic event (Dong X et al. Am. J. Hum. Genet. 2003 Feb;72(2):270-80). This alteration has been identified in multiple breast cancer cohorts as well as in controls (Shirts BH et al. Genet Med. 2016 10;18:974-81; Girard E et al. Int J Cancer. 2019 04;144:1962-1974; Dorling et al. N Engl J Med. 2021 02;384:428-439; Abdel-Razeq H et al. Front Oncol, 2022 Mar;12:673094; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This alteration was also seen in 0/732 breast cancer patients, 1/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). In a yeast in vivo study, p.R318H resulted in an intermediate response to DNA damage compared to wild-type (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21(12):2738-44). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 08, 2021 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2023 | Published functional studies are inconclusive: intermediate response to DNA damage (Roeb et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 26845104, 24728327, 12533788, 29872864, 28580595, 30303537, 35402282, 22419737, 19782031, 34933735, 33471991, 32658311, 35264596) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2020 | - - |
not specified Uncertain:1Other:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 07, 2020 | Variant summary: CHEK2 c.953G>A (p.Arg318His) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 256088 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CHEK2 causing Hereditary Breast and Ovarian Cancer Syndrome (5.5e-05 vs 0.00031), allowing no conclusion about variant significance. The variant has been reported in the literature in association with familial breast cancer and prostate cancer (Roeb_2012, Dong_2003, Haiman_2013, Shirts_2016, Xie_2018) and an in vitro functional assay demonstrated an intermediate level of DNA damage repair in yeast cells (Roeb_2012). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
CHEK2-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 30, 2024 | The CHEK2 c.953G>A variant is predicted to result in the amino acid substitution p.Arg318His. This variant has been reported in multiple individuals with breast cancer (Shirts et al. 2016. PubMed ID: 26845104; Xie et al. 2018. PubMed ID: 28580595; Guindalini et al. 2022. PubMed ID: 35264596; Abdel-Razeq et al. 2022. PubMed ID: 35402282) and at least one individual with colorectal cancer (Akcay et al. 2021. PubMed ID: 32658311); however, this variant has also been observed in multiple healthy control individuals with no reported cancer history (see for example, Girard et al. 2019. PubMed ID: 30303537; Breast Cancer Consortium et al. 2021. PubMed ID: 33471991). A yeast-based DNA-damage repair assay was inconclusive with the p.Arg318His allele retaining 47% residual activity relative to wild type (Table 1, Roeb et al. 2012. PubMed ID: 22419737). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD and is listed in ClinVar as a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/133890/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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 | May 30, 2022 | - - |
Familial cancer of breast;C0346629:Colorectal cancer;C0376358:Malignant tumor of prostate;C0585442:Bone osteosarcoma;C1836482:Li-Fraumeni syndrome 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jul 14, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at