chr22-28725254-G-A
Position:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM5PP3_ModeratePP5_Very_Strong
The NM_007194.4(CHEK2):c.433C>T(p.Arg145Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000514 in 1,613,910 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R145Q) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000052 ( 0 hom. )
Consequence
CHEK2
NM_007194.4 missense
NM_007194.4 missense
Scores
9
9
1
Clinical Significance
Conservation
PhyloP100: 3.37
Genes affected
CHEK2 (HGNC:16627): (checkpoint kinase 2) In response to DNA damage and replication blocks, cell cycle progression is halted through the control of critical cell cycle regulators. The protein encoded by this gene is a cell cycle checkpoint regulator and putative tumor suppressor. It contains a forkhead-associated protein interaction domain essential for activation in response to DNA damage and is rapidly phosphorylated in response to replication blocks and DNA damage. When activated, the encoded protein is known to inhibit CDC25C phosphatase, preventing entry into mitosis, and has been shown to stabilize the tumor suppressor protein p53, leading to cell cycle arrest in G1. In addition, this protein interacts with and phosphorylates BRCA1, allowing BRCA1 to restore survival after DNA damage. Mutations in this gene have been linked with Li-Fraumeni syndrome, a highly penetrant familial cancer phenotype usually associated with inherited mutations in TP53. Also, mutations in this gene are thought to confer a predisposition to sarcomas, breast cancer, and brain tumors. This nuclear protein is a member of the CDS1 subfamily of serine/threonine protein kinases. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM1
In a domain FHA (size 62) in uniprot entity CHK2_HUMAN there are 10 pathogenic changes around while only 2 benign (83%) in NM_007194.4
PM5
Other missense variant is known to change same aminoacid residue: Variant chr22-28725253-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.896
PP5
Variant 22-28725254-G-A is Pathogenic according to our data. Variant chr22-28725254-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5592.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-28725254-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHEK2 | NM_007194.4 | c.433C>T | p.Arg145Trp | missense_variant | 3/15 | ENST00000404276.6 | NP_009125.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHEK2 | ENST00000404276.6 | c.433C>T | p.Arg145Trp | missense_variant | 3/15 | 1 | NM_007194.4 | ENSP00000385747 | P2 |
Frequencies
GnomAD3 genomes 0.0000460 AC: 7AN: 152102Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
7
AN:
152102
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251290Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135806
GnomAD3 exomes
AF:
AC:
13
AN:
251290
Hom.:
AF XY:
AC XY:
8
AN XY:
135806
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000520 AC: 76AN: 1461808Hom.: 0 Cov.: 32 AF XY: 0.0000523 AC XY: 38AN XY: 727204
GnomAD4 exome
AF:
AC:
76
AN:
1461808
Hom.:
Cov.:
32
AF XY:
AC XY:
38
AN XY:
727204
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome 0.0000460 AC: 7AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74292
GnomAD4 genome
AF:
AC:
7
AN:
152102
Hom.:
Cov.:
32
AF XY:
AC XY:
4
AN XY:
74292
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ESP6500AA
AF:
AC:
0
ESP6500EA
AF:
AC:
1
ExAC
AF:
AC:
4
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:29Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:9
| Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2023 | CHEK2: PP1:Moderate, PS4:Moderate, PM2:Supporting, PS3:Supporting - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg | Nov 22, 2023 | This variant has been identified by standard clinical testing. female patient with metastatic breast cancer Selected ACMG criteria: Not enough evidence - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2024 | Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (PMID: 15535844, 22114986, 22419737, 26898890, 26786923, 35626031, 36551643, 38061684, 38520597); Published functional studies demonstrate a damaging effect: decreased or absent kinase activity, impaired KAP1 phosphorylation and CHK2 auto-phosphorylation, deficient response to DNA damage, and inability to bind BRCA1 and TP53 (PMID: 37449874, 11571648, 11390408, 11053450, 12049740, 22114986, 22419737, 30851065, 34903604); 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); Case-control data are inconclusive with respect to whether this variant is associated with breast cancer (PMID: 34903604, 35585550); This variant is associated with the following publications: (PMID: 22114986, 11053450, 17721994, 14569133, 15239132, 15876876, 12781359, 16732333, 15361833, 27067391, 11390408, 29479983, 28055978, 24549055, 30580288, 32805687, 31589614, 23334666, 15535844, 24728327, 12610780, 11298456, 10617473, 11901158, 11593395, 15818573, 16982735, 12654917, 12049740, 18996005, 18167186, 17380128, 15173168, 22189968, 21562711, 19338683, 15385111, 11719428, 11571648, 26786923, 26898890, 27751358, 26681312, 29520813, 29684080, 19782031, 28452373, 29146883, 29356917, 28152038, 28724667, 29909963, 30128536, 30851065, 31220302, 31398194, 30322717, 30676620, 30303537, 30967556, 31447099, 32906215, 32183364, 33634245, 31214711, 32710294, 32885271, 34903604, 28888541, 35264596, 32923877, 29922827, 35314380, 35585550, 35626031, 22419737, 33804961, 36493725, 36243179, 37449874, 36551643, 35988656, 34326862, 34482403, 38520597, 38918649, 38061684) - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 12, 2023 | The CHEK2 c.433C>T (p.Arg145Trp) variant has been reported in the published literature in individuals and families affected with breast and/or ovarian cancer (PMIDs: 36551643 (2022), 35264596 (2022), 35626031 (2022), 33471991 (2021), see also LOVD (https://databases.lovd.nl/shared/variants/CHEK2)), endometrial cancer (PMID: 26681312 (2015)), prostate cancer (PMID: 31214711 (2020)), testicular cancer (PMID: 30676620 (2019)), thyroid cancer (PMID: 29684080 (2018)), gastrointestinal cancer (PMID: 29684080 (2018)), and pancreatic cancer (PMID: 29520813 (2018)). In addition, multiple functional studies have shown that this variant results in a CHEK2 protein with decreased stability and an inability to bind and phosphorylate other proteins (PMIDs: 22419737 (2012), 16982735 (2006), 12049740 (2002), 11901158 (2002), 11719428 (2001), 11571648 (2001)). The frequency of this variant in the general population, 0.00016 (4/25120 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. 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, this variant is classified as likely pathogenic. - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Familial cancer of breast Pathogenic:8
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 24, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 145 of the CHEK2 protein (p.Arg145Trp). This variant is present in population databases (rs137853007, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 11719428, 15535844, 22419737, 29356917, 29909963). It has also been observed to segregate with disease in related individuals. This variant is also known as c.562C>T (p.Arg188Trp). ClinVar contains an entry for this variant (Variation ID: 5592). 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: 11298456, 11390408, 11571648, 11719428, 12049740, 15239132, 16982735). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine | Jan 30, 2018 | This c.562C>T (p.Arg188Trp) variant in the CHEK2 gene has been reported in multiple breast cancer patients [PMID: 11719428, 22419737] than that observed as extremely low in general population according to gnomad database. Functional studies showed that this mutant is defective of phosphorylation with significantly reduced kinase activity [PMID: 11053450, 11298456, 11390408, 11571648, 12049740, 22114986]. This variant has been observed for co-segregation with individuals affected by breast/lung cancers in a family with Li-Fraumeni syndrome. Multiple in silico predictions suggest this arginine to tryptophan is deleterious. Based upon above evidences, c.562C>T (p.Arg188Trp) variant in the CHEK2 gene is classified as likely pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Jul 02, 2018 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | May 31, 2022 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 11, 2022 | _x000D_ Criteria applied: PS3, PS4_MOD, PP3 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 28, 2016 | - - |
| Likely pathogenic, criteria provided, single submitter | research | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Dec 09, 2022 | PS3, PS4_STR, PP1 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 18, 2024 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:5
| Likely pathogenic, criteria provided, single submitter | research | Academic Department of Medical Genetics, University of Cambridge | Jan 26, 2018 | Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity. - |
| Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 10, 2021 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2023 | This missense variant replaces arginine with tryptophan at codon 145 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). Multiple functional studies have shown this variant to cause loss of CHEK2 kinase activity, DNA damage response, and cell cycle control function (PMID: 11053450, 11298456, 11390408, 11571648, 11719428, 22419737, 30851065, 34903604, 37449874). This reduced activity has been attributed to significantly reduced stability of the mutant protein (PMID: 12049740, 11719428, 16982735, 30851065, 34903604). This variant has been observed in over ten unrelated individuals affected with breast cancer (PMID: 11719428, 15535844, 26786923, 26898890, 29356917, 30303537, 32906215, 36551643, 37449874; Color internal data) and has been shown to segregate with breast cancer in three individuals in a family (PMID: 22419737). In a large case-control meta-analysis, this variant has been observed in 20/60466 breast cancer cases and 9/53461 unaffected controls (OR=1.965; 95%CI 0.895 to 4.316; p-value=0.096; Leiden Open Variation Database DB-ID CHEK2_000034) (PMID: 33471991). This variant has been identified in 14/282678 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 14, 2024 | The p.R145W variant (also known as c.433C>T), located in coding exon 2 of the CHEK2 gene, results from a C to T substitution at nucleotide position 433. The arginine at codon 145 is replaced by tryptophan, an amino acid with dissimilar properties. This variant is located in the FHA functional domain and multiple studies have demonstrated p.R145W abolishes normal CHK2 function, resulting in an unstable protein deficient in substrate binding/phosphorylation and overall DNA damage response (Lee SB et al. Cancer Res. 2001 Nov;61:8062-7; Falck J et al. Nature. 2001 Apr;410:842-7; Li J et al. Mol. Cell. 2002 May;9:1045-54). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat. 2019 May;40:631-648). This alteration was first described in a suspected Li-Fraumeni syndrome patient diagnosed with a sarcoma at age 20 and breast cancer at age 43, and was found to segregate with disease in a familial breast cancer kindred (Roeb W et al. Hum. Mol. Genet. 2012 Jun;21:2738-44). It was also identified in a patient with endometrial cancer referred for evaluation by an NGS hereditary cancer panel and in cohorts of breast cancer patients (Susswein LR et al. Genet. Med. 2016 Aug;18(8):823-32; Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119; Caminsky NG et al. Hum. Mutat. 2016 07;37(7):640-52; Fan Z et al. Breast Cancer Res. Treat. 2018 May;169(1):59-67; Dorling et al. N Engl J Med. 2021 02;384:428-439; Greville-Heygate SL et al. JCO Precis Oncol, 2020 May;4:; Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190; Espinel W et al. Cancers (Basel), 2022 May;14:; Nurmi AK et al. Cancers (Basel), 2022 Dec;14:; Godinez Paredes JM et al. Breast Cancer Res Treat, 2024 Mar;:). Further, this alteration was detected in the germline of a patient diagnosed with a cervical chordoma undergoing paired germline and somatic testing by whole exome sequencing (Gröschel S et al. Nat Commun. 2019 04;10:1635). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Apr 08, 2019 | - - |
Li-Fraumeni syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 23, 2022 | Variant summary: CHEK2 c.433C>T (p.Arg145Trp) results in a non-conservative amino acid change located in the forkhead-associated (FHA) domain (IPR000253) of 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 5.2e-05 in 251290 control chromosomes (gnomAD v2.1, exomes dataset). The observed variant frequency is approximately 1.8-fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Li-Fraumeni Syndrome phenotype (2.8e-05), suggesting that the variant could be benign. However, c.433C>T has been reported in the literature in individuals affected with multiple cancers that are suggestive of Li-Fraumeni Syndrome (e.g. Lee_2001, Roeb_2012), and in at least one of these families, the variant segregated with disease in individuals who were genotyped (Roeb_2012). The variant has also been detected in individuals with other cancer phenotypes, including breast, ovarian, and prostate cancer (e.g. Friedrichsen_2004, Carter_2018, Fan_2018, Wu_2018, Girard_2019, Momozawa_2020, Vargas-Parra_2020, AbouAlaiwi_2021, Greville-Heygate_2020). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 20/60466 cases, and was also found in 9/53461 controls, suggesting an association with increased breast cancer risk (Odds Ratio: 1.96, 95% CI: 0.89-4.32, P = 0.0925) for the variant (Dorling_2021, Boonen_2022). Several publications report experimental evidence evaluating an impact on protein function, demonstrating reduced protein stability and decreased CHEK2 function (e.g. Lee_2001, Li_2002, Roeb_2012, Delimitsou_2019, Boonen_2022). Fifteen other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and all of them classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Li-Fraumeni syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Feb 07, 2023 | _x000D_ Criteria applied: PS4, PS3_SUP, PP3 - |
Li-Fraumeni syndrome 2 Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 15, 2001 | - - |
Breast and/or ovarian cancer Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 27, 2023 | - - |
CHEK2-related cancer predisposition Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The CHEK2 c.433C>T (p.Arg145Trp) missense variant has been identified in a heterozygous state in seven individuals with various types of cancer, including breast, colon, lung, and Li-Fraumeni syndrome (Bell et al. 1999; Lee et al. 2001; Friedrichsen et al. 2004; Roeb et al. 2012). The p.Arg145Trp variant was absent from 659 controls and is reported at a frequency of 0.00003 in the total population of the Exome Aggregation Consortium. Functional studies in cell lines and yeast cells demonstrated that p.Arg145Trp-CHEK2 protein has a reduced half-life compared with wild type CHEK2 and does not become activated in response to DNA damage (Lee et al. 2001; Falck et al. 2001; Li et al. 2002; Sodha et al. 2006; Roeb et al. 2012). Based on the evidence, the p.Arg145Trp variant is classified as likely pathogenic for CHEK2-related cancer susceptibility. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Gastric cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory for Genotyping Development, RIKEN | Jul 01, 2021 | - - |
Malignant tumor of breast Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The CHEK2 p.Arg145Trp variant was identified in 5 of 4460 proband chromosomes (frequency: 0.001) from individuals or families with breast and ovarian cancer, Li Fraumeni syndrome, or neoblastoma and was present in 1 of 3306 control chromosomes (frequency: 0.0003) from healthy individuals (Caminsky 2016, Castera 2014, Desrichard 2011, Friedrichsen 2004, Pugh 2013, Bodian 2014). The variant was also identified in dbSNP (ID: rs137853007) as “With Likely benign, Pathogenic allele”, ClinVar (classified as likely pathogenic by Ambry Genetics, Invitae, Counsyl, Color Genomics, Laboratory Corporation of America, and GeneDx; and as pathogenic by OMIM), Cosmic, MutDB, and Zhejiang Colon Cancer Database. The variant was identified in control databases in 12 of 277018 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 2 of 34420 chromosomes (freq: 0.0001), European in 5 of 126526 chromosomes (freq: 0.00004), Finnish in 4 of 25790 chromosomes (freq: 0.0002), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while it was not observed in the African, Other, Ashkenazi Jewish, or East Asian populations. The p.Arg145 residue is conserved in mammals but not in more distantly related organisms, and four out of five 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. Several in vitro and in vivo functional studies have shown the variant have reduced catalytic activity and disrupted kinase activity (Falck 2001, Wu 2001, Desrichard 2011, Lee 2001). In addition, this variant produces an unstable protein which is neither activated upon ionizing radiation, nor is it able to bind to the p53 substrate (Falck 2001, Lee 2001, Wu 2001, Kilpivaara 2004, Sodha 2006, Roeb 2012). This variant has been shown to segregate with breast or lung cancer in 4 members of one family (Roeb 2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. - |
not specified Other:1
| not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;D;.;D;.;.;.;D;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Pathogenic
.;D;.;.;D;D;.;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;M;M;M;.;M;M;.;.;.;.;.
MutationTaster
Benign
A;A;A;A;A;A;A;A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;D;D;D;.;D;D;D;.;.;.
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;.;D;D;D;.;.;.
Sift4G
Uncertain
D;D;D;D;D;.;D;D;D;D;.;.
Polyphen
D;D;D;D;D;D;D;.;.;.;.;.
Vest4
MVP
MPC
0.17
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at