Submissions for variant NM_007194.4(CHEK2):c.1238del (p.Ser412_Leu413insTer)

dbSNP: rs765664259

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000575173	SCV000913578	pathogenic	Hereditary cancer-predisposing syndrome	2018-03-25	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001788289	SCV002030127	likely pathogenic	Li-Fraumeni syndrome 2	2021-07-13	criteria provided, single submitter	clinical testing	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Ambry Genetics	RCV000575173	SCV002662340	pathogenic	Hereditary cancer-predisposing syndrome	2019-03-20	criteria provided, single submitter	clinical testing	The c.1238delT pathogenic mutation (also known as p.L413*), located in coding exon 10 of the CHEK2 gene, results from a deletion of one nucleotide at nucleotide position 1238. This changes the amino acid from a leucine to a stop codon within coding exon 10. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV003228957	SCV003926339	likely pathogenic	not provided	2022-11-18	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in an individual with breast cancer (Weitzel et al., 2019); This variant is associated with the following publications: (PMID: 31206626, 29922827)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003230542	SCV003928336	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-20	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1238delT (p.Leu413X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant was absent in 250208 control chromosomes (gnomAD). c.1238delT has been reported in the literature in individuals affected with Breast Cancer (e.g. Quezada Urban_2018, Weitzel_2019, Gomez-Flores-Ramos_2022). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and two as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003335488	SCV004043315	pathogenic	Familial cancer of breast	2023-06-28	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003228957	SCV004221719	pathogenic	not provided	2022-10-07	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the CHEK2 mRNA and causes the premature termination of CHEK2 protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in an individual with breast cancer (PMID: 31206626 (2019)). Based on the available information, this variant is classified as pathogenic.
Invitae	RCV003335488	SCV004304213	pathogenic	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu413*) in the CHEK2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CHEK2 are known to be pathogenic (PMID: 21876083, 24713400). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 31206626). ClinVar contains an entry for this variant (Variation ID: 479550). For these reasons, this variant has been classified as Pathogenic.