Submissions for variant NM_007194.4(CHEK2):c.1555C>T (p.Arg519Ter)

dbSNP: rs200432447

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212474	SCV000149914	likely pathogenic	not provided	2023-01-11	criteria provided, single submitter	clinical testing	Nonsense variant in the C-terminus predicted to result in protein truncation, as the last 25 amino acids are lost, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with breast, ovarian, prostate, and other cancers (Maxwell et al., 2015; Tung et al., 2015; Yorczyk et al., 2015; Matejcic et al., 2020; Ryu et al., 2020; Akamatsu et al., 2022); Published functional studies are inconclusive: demonstrate intermediate impact on phosphorylation compared to wildtype (Boonen et al., 2022); This variant is associated with the following publications: (PMID: 26681312, 29520813, 12909615, 24879340, 25503501, 25318351, 27751358, 29020732, 18004398, 29308099, 25186627, 30680046, 30287823, 30293905, 32805687, 22419737, 32832836, 32980694, 32761968, 34204722, 32322110, 32172797, 35118230, 32019277, 34903604)
Ambry Genetics	RCV000116005	SCV000215386	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing	The p.R519* pathogenic mutation (also known as c.1555C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1555. This changes the amino acid from an arginine to a stop codon within coding exon 14. This alteration occurs at the 3' terminus of theCHEK2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 25 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data; Zannini L et al. J. Biol. Chem. 2003 Oct;278:42346-51). This mutation has been reported in the literature in breast cancer and prostate cancer cohorts (Yorczyk A et al. Clin. Genet. 2015 Sep;88:278-82; Maxwell K et al. Genet. Med. 2015 Aug;17:630-8; Wu Y et al. Prostate 2018 06;78(8):607-615; Fonfria M et al. J Pers Med 2021 Jun;11(6). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210124	SCV000266167	likely pathogenic	Breast and colorectal cancer, susceptibility to	2017-07-11	criteria provided, single submitter	clinical testing
Invitae	RCV000471222	SCV000550494	likely pathogenic	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg519*) in the CHEK2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 25 amino acid(s) of the CHEK2 protein. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 25186627, 25503501, 27751358, 29020732, 29520813, 30287823, 30680046, 32761968). ClinVar contains an entry for this variant (Variation ID: 128064). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 34903604). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). This variant disrupts the nuclear localization signal (NLS) of the CHEK2 protein, which is critical for proper nuclear localization (PMID: 18004398, 12909615). While functional studies have not been performed to directly test the effect of this variant on CHEK2 protein function, this suggests that disruption of this region of the protein is causative of disease. 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.
Color Diagnostics, LLC DBA Color Health	RCV000116005	SCV000689671	pathogenic	Hereditary cancer-predisposing syndrome	2022-09-12	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 15 of the CHEK2 gene, creating a premature translation stop signal in the last coding exon. The mutant transcript is likely to escape nonsense-mediated decay and expressed as a truncated protein that lacks the functionally important nuclear localization signal (PMID: 12909615, 16798742, 24879340). This variant has been reported in seven individuals affected with breast cancer, including two individuals having a family history of breast or colorectal cancer (PMID: 25503501, 25318351, 30287823; Color internal data) and in an individual affected with ovarian cancer with a family history colorectal cancer (PMID: 29020732). This variant has also been reported individuals affected with uterine cancer (PMID: 30680046) and prostate cancer (PMID: 29520813), and in four unaffected individuals (PMID: 30287823). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589100	SCV000698785	pathogenic	Hereditary breast ovarian cancer syndrome	2020-11-19	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1555C>T (p.Arg519X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.3e-06 in 232840 control chromosomes (gnomAD). c.1555C>T has been reported in the literature in multiple individuals affected with colon cancer, prostate cancer, breast cancer and/or ovarian cancer (Yorczyk_2014, Maxwell_2014, Susswein_2015, Velho_2019, Ryu_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (1x) and likely pathogenic (5x). Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl	RCV000471222	SCV000786152	likely pathogenic	Familial cancer of breast	2018-03-06	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212474	SCV001470305	likely pathogenic	not provided	2023-07-25	criteria provided, single submitter	clinical testing	The CHEK2 c.1555C>T (p.Arg519*) variant is not predicted to cause nonsense-mediated decay, however it may negatively impact protein function due to the partial loss of the nuclear localization signal that is located within the truncated 25 amino acids (PMID: 24879340 (2014), 22419737 (2012), 12909615 (2003)). In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32805687 (2020), 32761968 (2020), 30287823 (2018), 25503501 (2015), 25318351 (2014)), ovarian cancer (PMID: 29020732 (2018), prostate cancer (PMID: 29520813 (2018)), and colorectal cancer (PMID: 26681312 (2015)). The frequency of this variant in the general population, 0.000099 (1/10138 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001705822	SCV001934350	likely pathogenic	Li-Fraumeni syndrome 2	2020-12-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000471222	SCV001934497	likely pathogenic	Familial cancer of breast	2021-03-24	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798352	SCV002043396	likely pathogenic	Breast and/or ovarian cancer	2020-09-17	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000116005	SCV002537393	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-07	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000471222	SCV004020188	pathogenic	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Breast Care Center, Daerim St. Mary`s Hospital	RCV000116005	SCV004021929	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-07-25	criteria provided, single submitter	clinical testing	The CHEK2:c.1555C>T (p.Arg519*) variant was located in the last coding exon 15 of the CHEK2 gene, which predicts a truncation to lead to a nonsense codon, resulting in a null variant. This type of variant is a known mechanism of disease. It was rarely reported in the gnomAD population database. This likely pathogenic variant was detected in a 73-year-old Korean female diagnosed with hormone-positive and invasive breast cancer. The patient had a first-degree family member with pancreatic cancer in their 70s.
Baylor Genetics	RCV000471222	SCV004217492	pathogenic	Familial cancer of breast	2023-10-20	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000212474	SCV001978188	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212474	SCV001979566	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000471222	SCV002588979	pathogenic	Familial cancer of breast	2022-08-26	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162543	SCV002758512	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research