Submissions for variant NM_007194.4(CHEK2):c.520C>T (p.Leu174Phe)

gnomAD frequency: 0.00001  dbSNP: rs876659400

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221904	SCV000276471	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-08	criteria provided, single submitter	clinical testing	The p.L174F variant (also known as c.520C>T), located in coding exon 3 of the CHEK2 gene, results from a C to T substitution at nucleotide position 520. The leucine at codon 174 is replaced by phenylalanine, an amino acid with highly similar properties. In one study, this variant was reported in 1 of 673 sporadic breast cancer patients and was not reported in 683 non-cancer controls (Kleibl Z et al. Breast Cancer Res. Treat., 2008 Nov;112:159-64). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J Med Genet, 2017 11;54:732-741). This alteration behaved as functional in an in vivo, yeast-based growth rate assay. (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This variant was also observed in 1/3251 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). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx	RCV000223554	SCV000278921	uncertain significance	not provided	2023-08-03	criteria provided, single submitter	clinical testing	Observed in individuals with breast cancer (Kleibl et al., 2008; Lerner-Ellis et al., 2021); Published functional studies assessing DNA damage response demonstrate cell growth comparable to wild type in a yeast-based assay (Delimitsou et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 36980535, 19782031, 22419737, 27009842, 18058223, 30851065, 32885271, 28779002)
Invitae	RCV000469289	SCV000550468	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 174 of the CHEK2 protein (p.Leu174Phe). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with breast cancer and/or neuroblastoma (PMID: 18058223, 27009842). This variant is also known as c.649C>T (p.L217F). ClinVar contains an entry for this variant (Variation ID: 232352). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000221904	SCV001359141	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-18	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 174 of the CHEK2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A functional study reported this variant as functional in a yeast based DNA damage response assay (PMID: 30851065) and a human cell complementation assay showed no impact on KAP1 phosphorylation and intermediate impact on CHEK2 autophosphorylation (PMID: 37449874). This variant has been reported in individuals affected with breast cancer in the literature (PMID: 18058223, 37449874). This variant has been identified in 3/277196 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000469289	SCV001368818	uncertain significance	Familial cancer of breast	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP4.
MGZ Medical Genetics Center	RCV000469289	SCV002579089	uncertain significance	Familial cancer of breast	2022-05-04	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000223554	SCV003832005	uncertain significance	not provided	2019-05-02	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000469289	SCV004217536	uncertain significance	Familial cancer of breast	2023-09-25	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000223554	SCV001552604	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CHEK2 p.Leu174Phe variant was identified in 1 of 1346 proband chromosomes (frequency: 0.0007) from Czech individuals or families with breast cancer and was not identified in 1366 control chromosomes from healthy individuals (Kleibl 2008). The variant was also identified in dbSNP (ID: rs876659400) “With Uncertain significance allele”, and ClinVar (classified as uncertain significance; submitters: Ambry Genetics, GeneDx and Invitae). The variant was identified in control databases in 3 of 277196 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017), observed in the following populations: Latino in 2 of 34420 chromosomes (freq: 0.00006) and East Asian in 1 of 18868 chromosomes (freq: 0.00005) while not observed in the African, Other, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The variant is located in the FHA (forkhead-associated) functional domain of the CHEK2 protein. The p.Leu174 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the variant Phe to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.