rs373073383
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_007194.4(CHEK2):c.1175C>T(p.Ala392Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. A392E) has been classified as Uncertain significance.
Frequency
Consequence
NM_007194.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CHEK2 | NM_007194.4 | c.1175C>T | p.Ala392Val | missense_variant | 11/15 | ENST00000404276.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CHEK2 | ENST00000404276.6 | c.1175C>T | p.Ala392Val | missense_variant | 11/15 | 1 | NM_007194.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251060Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135722
GnomAD4 exome AF: 0.0000513 AC: 75AN: 1461428Hom.: 0 Cov.: 31 AF XY: 0.0000426 AC XY: 31AN XY: 727028
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74336
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 29, 2022 | The frequency of this variant in the general population, 0.000062 (7/113398 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 35127508 (2021), 34011307 (2021), 29752822 (2018), 28779002 (2017), 19656415 (2009)) and in unaffected individuals (PMID: 28779002 (2017)). In a large breast cancer association study, the variant was found in both affected and unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/CHEK2). Functional studies on yeast and mouse models show this variant has a damaging effect on protein function (PMID: 34903604 (2021), 30851065 (2019)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 22, 2021 | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer in published literature (Soumittra 2009, Decker 2017, Hauke 2018, Li 2019); Published functional studies demonstrate damaged protein function in vivo (Delimitsou 2019); This variant is associated with the following publications: (PMID: 19656415, 22920209, 26466571, 28743916, 29522266, 29752822, 31398194, 30851065, 28779002, 29021619) - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2022 | CHEK2: PS3, BP1 - |
Familial cancer of breast Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 13, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 27, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 392 of the CHEK2 protein (p.Ala392Val). This variant is present in population databases (rs373073383, gnomAD 0.008%). This missense change has been observed in individual(s) with breast cancer (PMID: 19656415, 29752822, 34011307, 34326862). ClinVar contains an entry for this variant (Variation ID: 141136). 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 disruptive. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 28743916, 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Apr 08, 2019 | - - |
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | May 04, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 10, 2019 | Variant summary: CHEK2 c.1175C>T (p.Ala392Val) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.6e-05 in 251060 control chromosomes. c.1175C>T has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, lung cancer, melanoma (Soumittra_2009, Guauque-Olarte_2016, Riaz_2017, Li_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. At least one publication reports experimental evidence evaluating an impact on protein function and showed that this variant had damaging effect (Delimitsou_2019). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS. - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2024 | The p.A392V variant (also known as c.1175C>T), located in coding exon 10 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1175. The alanine at codon 392 is replaced by valine, an amino acid with similar properties. Across studies, this alteration has been identified in both breast cancer cases and unaffected controls (Soumittra N et al. Hered. Cancer Clin. Pract. 2009 Aug;7:13; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Li JY et al. Int. J. Cancer, 2019 01;144:281-289; Zografos E et al. Genes (Basel), 2022 Jul;13; Zografos E et al. BMC Cancer, 2021 May;21:572; Andrikopoulou A et al. Front Oncol, 2021 Jan;11:797505; Hauke J et al. Cancer Med. 2018 Apr;7(4):1349-1358). In a large study, this variant was reported in 15/60,466 breast cancer cases and in 4/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This alteration was reported as damaging in an mES cell-based assay of CHEK2 activity (Boonen RACM et al. Cancer Res, 2022 02;82:615-631) and non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This alteration was also reported as functionally impaired in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res. 2023 Aug;29(16):3037-3050). 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 | Oct 04, 2023 | This missense variant replaces alanine with valine at codon 392 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Experimental functional studies have demonstrated this variant to be damaging in a yeast DNA damage repair assay (PMID: 30851065), deficient in Ser516 autophosphorylation (PMID: 28743916, 37449874) and Kap1 p.S473 phosphorylation in cell-based kinase assays (PMID: 34903604, 37449874). This variant has been reported in individuals affected with breast cancer (PMID: 19656415, 29522266, 29752822, 33471991, 34011307) and was associated with a risk of breast cancer in a case-control study (PMID: 33471991; observed in 15/60,466 women with breast cancer and 4/53,461 controls). This variant has also been identified in 9/251060 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been observed in an individual over 70 with no personal history of cancer (FLOSSIES; https://whi.color.com/). 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. - |
Li-Fraumeni syndrome 2 Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, HCU Lozano Blesa | May 01, 2023 | Variant summary: CHEK2 c.1175C>T results in the replacement of Ala392 by a Val residue (p.Ala392Val). The variant was identified in 1 out of 396 patients analysed (freq: 0.0025, doi: 10.3389/fgene.2023.1274108). The patient was a woman that developed breast cancer at the age of 38 years (luminal-B tumor phenotype). Two second-degree relatives were also diagnosed with BC, although a co-segregation study could not be performed. Ala392 is located in the kinase domain, is part of the conserved APE motif (Ala392–Pro393–Glu394) located in the long T-loop. The substitution of Ala392 by valine introduces a bulkier residue at a spot where Ala392 appears to be in close contact with some residues at the dimerization interface, particularly with Arg474. It may affect the protein integrity and thus its function. The variant is reported in gnomAD v4 in 78 cases out of 1613584 alleles analysed (freq=4.8x10-3 %). In ClinVar more than a dozen of reports appear classifying the variant as of Uncertain significance. Other replacements found at this position (A392G, A392T, A392P, and A392E) are also classified by ClinVar as of Uncertain Significance. The metapredictor PirePred (relies on verdicts from other 15 predictor or metapredictor tools) and the AI-based predictor AlphaMissense classify Ala392Val as Pathogenic, whereas the ACMG classification tool Franklin suggests this variant as VUS (Uncertain Significance). Our in-silico study on the protein stability based on relaxation molecular dynamics simulations (doi: 10.3389/fgene.2023.1274108) indicates that Ala392Val induces conformational unstability on CHEK2 protein. Moreover, Stolarova L. et al’s functional study on KAP1 phosphorylation and CHEK2 autophosphorylation protein capability reports this variant as functionally impaired (PMID: 37449874). With all this information, we believe this variant have more chances of being Pathogenic. - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | curation | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Jan 09, 2024 | . According to the ACMG standard criteria we chose these criteria: PS3 (strong pathogenic): Delimitsou (2019): damaging in yeast assay Stolarova (2023): damaging in CHK2 & KAP1 assay Boonen (2022): damaing in KAP1 assay , PS4 (supporting pathogenic): OR in Stolarova et al. 2.5 but not significant (p=0.07) and CI intervall including 1.0; 18 Families in GC-HBOC only 1X in gnomAD V3.1.2 non Cancer, PP3 (supporting pathogenic): REVEL: 0.825 [cutoff REVEL >0.7333] - |
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.Ala392Val variant was identified in 1 of 182 proband chromosomes (frequency: 0.005) from individuals or families with early onset breast or ovarian cancer (Soumittra 2009 PMID: 19656415). The variant was also identified in dbSNP (ID: rs373073383 as With Uncertain significance allele), ClinVar (5x as a variant of uncertain significance), and Cosmic (1x). The variant was not identified in MutDB or the Zhejiang University Database. The variant was identified in control databases in 11 of 245912 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 9 of 111392 chromosomes (freq: 0.00008), East Asian in 1 of 17248 chromosomes (freq: 0.00006), and Finnish in 1 of 22300 chromosomes (freq: 0.00005), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, and South Asian populations. The p.Ala392 residue is conserved across mammals and other organisms, and 4 out of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; however, this is not reliably predictive of pathogenicity. 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