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

gnomAD frequency: 0.00007  dbSNP: rs201084748

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129718	SCV000184521	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-08	criteria provided, single submitter	clinical testing	The p.S5L variant (also known as c.14C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 14. The serine at codon 5 is replaced by leucine, an amino acid with dissimilar properties. This variant has been identified in multiple breast cancer and control cohorts across studies (Le Calvez-Kelm F et al. Breast Cancer Res., 2011 Jan;13:R6; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Decker B et al. J. Med. Genet., 2017 11;54:732-741; Hauke J et al. Cancer Med, 2018 04;7:1349-1358). This alteration was also observed in one ovarian cancer patient in a cohort of 3251 individuals who met eligibility criteria for hereditary breast and ovarian cancer syndrome (Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). In addition, this variant was identified in a cohort of 681 ancestrally diverse, healthy subjects (Bodian DL et al. PLoS One, 2014 Apr;9:e94554). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis and behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000656829	SCV000211004	uncertain significance	not provided	2022-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, colorectal, and other cancers, as well as unaffected controls (Le Calvez-Kelm et al., 2011; Yurgelun et al., 2015; Decker et al., 2017; Yurgelun et al., 2017; Hauke et al., 2018); Published functional studies demonstrate cell growth comparable to wild-type in an in vivo yeast-based assay (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 24728327, 26787654, 21244692, 28135145, 25980754, 28102005, 29522266, 28779002, 30851065, 35643632, 32885271, 36315097)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196102	SCV000254927	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 5 of the CHEK2 protein (p.Ser5Leu). This variant is present in population databases (rs201084748, gnomAD 0.02%). This missense change has been observed in individual(s) with CHEK2-related conditions (PMID: 21244692, 25980754, 28135145, 29522266). ClinVar contains an entry for this variant (Variation ID: 133886). 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 tolerated. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 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.
Counsyl	RCV000196102	SCV000785867	uncertain significance	Familial cancer of breast	2017-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129718	SCV000902865	likely benign	Hereditary cancer-predisposing syndrome	2015-08-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120550	SCV001737865	uncertain significance	not specified	2024-03-24	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.14C>T (p.Ser5Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.9e-05 in 245168 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome (6.9e-05 vs 0.00031), allowing no conclusion about variant significance. c.14C>T has been reported in the literature in individuals affected with breast cancer as well as unaffected controls and as a VUS in settings of multigene panel testing on individuals with colorectal cancer (example, Calvez-Kelm_2011, Yurgelun_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant in a yeast functional experimental system evaluating the ability to repair MMS (methyl-methanesulfonate) induced DNA damage (Delimitsou_2019). The following publications have been ascertained in the context of this evaluation (PMID: 21244692, 30851065, 28135145). ClinVar contains an entry for this variant (Variation ID: 133886). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656829	SCV002046597	likely benign	not provided	2023-07-31	criteria provided, single submitter	clinical testing	A yeast-based study indicates the variant had neutral effects on CHEK2 protein function (PMID: 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 benign. Taking into account the available information, we are unable to determine the clinical significance of this variant.
Myriad Genetics, Inc.	RCV000196102	SCV004020181	likely benign	Familial cancer of breast	2023-03-09	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
ITMI	RCV000120550	SCV000084704	not provided	not specified	2013-09-19	no assertion provided	reference population
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355777	SCV001550755	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Ser5Leu variant was identified in 2 of 2606 proband chromosomes (frequency: 0.001) from individuals or families with breast cancer and was present in 1 of 2218 control chromosomes (frequency: 0.001) from healthy individuals (Le Calvez-Kelm 2011). The variant was also identified in the following databases: dbSNP (ID: rs201084748) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae), Clinvitae (classified as uncertain significance by ClinVar, Invitae). The variant was not identified in Cosmic, MutDB, Zhejiang Colon Cancer Database, databases. The variant was identified in control databases in 16 of 239848 chromosomes at a frequency of 0.0001 in the following populations: European in 12 of 106232 chromosomes (freq.0.0001), African in 3 of 14996 chromosomes (freq. 0.0002), Asian in 1 of 30688 chromosomes (freq. 0.00003) (Genome Aggregation Consortium Feb 27, 2017). The p.Ser5 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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. 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.