22-28695786-C-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM1
The ENST00000404276.6(CHEK2):c.1183G>C(p.Val395Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. V395F) has been classified as Uncertain significance.
Frequency
Consequence
ENST00000404276.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1183G>C | p.Val395Leu | missense_variant | 11/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1183G>C | p.Val395Leu | missense_variant | 11/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 251068Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135724
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461616Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727118
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152210Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74360
ClinVar
Submissions by phenotype
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Mar 09, 2023 | This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 07, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 02, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 25, 2024 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 395 of the CHEK2 protein (p.Val395Leu). This variant is present in population databases (rs587780170, gnomAD 0.007%). This missense change has been observed in individual(s) with colorectal cancer and/or ovarian cancer (PMID: 28135145, 31050813). ClinVar contains an entry for this variant (Variation ID: 128049). 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 does not substantially affect CHEK2 function (PMID: 30851065). 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. - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 11, 2023 | Variant summary: CHEK2 c.1183G>C (p.Val395Leu) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251068 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1183G>C has been reported in the literature as a VUS in settings of multigene panel testing in individuals affected with breast and/or colorectal cancer (example, Yurgelun_2017, Kleibova_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function (example, Delimitsou_2019). These results showed no damaging effect of this variant in ability of CHEK2 to repair MMS induced DNA damage in a yeast based cell system. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as VUS (n=8) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 10, 2022 | The CHEK2 c.1183G>C; p.Val395Leu variant (rs587780170) is reported in the literature in an individual with colorectal cancer (Yurgelun 2017) and an individual with ovarian cancer (Kleiblova 2019). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 128049). One functional in vivo yeast-based assay showed the variant to be neutral (Delimitsou 2019). However, in vitro and cell-based kinase assays the variant was shown to be deleterious (Kleiblova 2019). This variant is found in the general population with an overall allele frequency of 0.003% (7/251068 alleles) in the Genome Aggregation Database. The valine at codon 395 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.478). Based on available information, the clinical significance of this variant is uncertain at this time. References: Delimitsou A et al. Functional characterization of CHEK2 variants in a Saccharomyces cerevisiae system. Hum Mutat. 2019 May;40(5):631-648. PMID: 30851065. Kleiblova P et al. Identification of deleterious germline CHEK2 mutations and their association with breast and ovarian cancer. Int J Cancer. 2019 Oct 1;145(7):1782-1797. PMID: 31050813. Yurgelun MB et al. Cancer Susceptibility Gene Mutations in Individuals With Colorectal Cancer. J Clin Oncol. 2017 Apr 1;35(10):1086-1095. PMID: 28135145. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 06, 2024 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with colon, ovarian, and other cancers, and also in unaffected controls (PMID: 28135145, 31050813); Published functional studies showed no impact on DNA damage response in yeast-based assays, while a human cell-based assay demonstrated defective kinase activity (PMID: 30851065, 31050813); This variant is associated with the following publications: (PMID: 28135145, 30851065, 31050813, 32295079, Ozair2021[Abstract], Dosunmu2021[Abstract], 34628056, 28779002, 19782031, 22419737) - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2023 | The p.V395L variant (also known as c.1183G>C), located in coding exon 10 of the CHEK2 gene, results from a G to C substitution at nucleotide position 1183. The valine at codon 395 is replaced by leucine, an amino acid with highly similar properties. This alteration has been identified in both individuals with breast cancer and healthy controls (Decker B et al. J Med Genet, 2017 11;54:732-741). Functional analyses of this allele have produced conflicting results (Delimitsou A et al. Hum Mutat, 2019 05;40:631-648; Kleiblova P et al. Int J Cancer, 2019 10;145:1782-1797). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 16, 2022 | This missense variant replaces valine with leucine at codon 395 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). Functional studies have shown this variant to have deleterious effect on CHEK2 function in in vitro and cell-based kinase assays but have neutral effect in yeast-based DNA damage repair assays (PMID 30851065, 31050813). In a large breast cancer case-control study, this variant has been observed in 11/60455 cases and 7/53454 controls (OR=1.389, 95%CI [0.539 to 3.585], p-value=0.638) (PMID: 33471991). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). This variant has been identified in 7/251068 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. - |
Breast and/or ovarian cancer Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
CHEK2-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 14, 2024 | The CHEK2 c.1183G>C variant is predicted to result in the amino acid substitution p.Val395Leu. This variant was previously reported in individuals with cancer, including colorectal or ovarian cancer (see, for example, Yurgelun et al. 2017. PubMed ID: 28135145; Kleiblova et al. 2019. PubMed ID: 31050813, see supplementary table S3). However, in one breast cancer cohort study, this variant was present in both affected individuals and healthy controls (Dorling et al. 2021. PubMed ID: 33471991, supplementary data, reported as chr22_29091774_C_G). Additionally, a functional analysis of the p.Val395Leu variant protein in a yeast model indicated that this change may be benign (Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0062% of alleles in individuals of African descent in gnomAD and is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/128049/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Sep 09, 2024 | According to the ACMG SVI adaptation criteria we chose this criterion: PS3 (strong pathogenic): Stolarova 2023: damaging bei CHK2 und KAP-Assay; Kleiblova 2019: damaging bei KAP1- und Omnia Kinase Assay; Delimitsou 2019: benign - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at