ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.14C>T (p.Ser5Leu) (rs201084748)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129718 SCV000184521 uncertain significance Hereditary cancer-predisposing syndrome 2017-03-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
GeneDx RCV000656829 SCV000211004 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.14C>T at the cDNA level, p.Ser5Leu (S5L) at the protein level, and results in the change of a Serine to a Leucine (TCG>TTG). This variant has been observed in individuals with breast cancer, colon cancer, and in at least three individuals with a Lynch syndrome-associated cancer and/or polyps (Le Calvez-Kelm 2011, Yurgelun 2015, Yurgelun 2017, Decker 2017, Hauke 2018). However, this variant has also been identified in healthy individuals (Le Calvez-Kelm 2011, Bodian 2014, Decker 2017). Of note, the participants in Bodian et al. (2014) were younger than 50 years old thus the unaffected status of this individual may not be significant. CHEK2 Ser5Leu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Ser5Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000196102 SCV000254927 uncertain significance Familial cancer of breast 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 5 of the CHEK2 protein (p.Ser5Leu). The serine residue is weakly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs201084748, ExAC 0.008%). This variant has been reported in an individual with colorectal cancer (PMID: 28135145), two individuals affected with breast cancer, several individuals undergoing testing for Lynch syndrome (PMID: 25980754), and an unaffected control (PMID: 21244692). ClinVar contains an entry for this variant (Variation ID: 133886). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000196102 SCV000785867 uncertain significance Familial cancer of breast 2017-12-20 criteria provided, single submitter clinical testing
Color RCV000129718 SCV000902865 likely benign Hereditary cancer-predisposing syndrome 2015-08-13 criteria provided, single submitter clinical testing
ITMI RCV000120550 SCV000084704 not provided not specified 2013-09-19 no assertion provided reference population

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