Submissions for variant NM_007194.4(CHEK2):c.549G>C (p.Leu183Phe)

gnomAD frequency: 0.00001  dbSNP: rs745646057

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164270	SCV000214895	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-20	criteria provided, single submitter	clinical testing	The p.L183F variant (also known as c.549G>C), located in coding exon 3 of the CHEK2 gene, results from a G to C substitution at nucleotide position 549. The leucine at codon 183 is replaced by phenylalanine, an amino acid with highly similar properties. This alteration has been detected in four, apparently non-related, Greek breast cancer families (Fostira F et al. J Med Genet. 2020 01;57:53-61). 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), and was detected in 1/1185 Italian patients with a personal and/or family history breast, ovarian or prostate cancer (Toss A et al. Genes (Basel), 2021 Apr;12). This alteration was seen in 6/732 breast cancer patients, 2/189 colorectal cancer patients and 1/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This alteration has also been detected in two patients with colorectal cancer and classified as a variant of uncertain significance by the authors (Shirts BH et al. Genet Med. 2016 10;18:974-81). This alteration behaved as non-functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum Mutat. 2019 05;40:631-648). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000210079	SCV000266169	uncertain significance	Breast and colorectal cancer, susceptibility to	2015-11-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000221179	SCV000279299	uncertain significance	not provided	2022-06-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies suggest a damaging effect: large decrease in growth rate after DNA damage compared to wildtype (Delimitsou 2019); Identified in patients with a personal history of breast cancer and/or a family history of other cancers in published literature (Shirts 2016, Delimitsou 2019, Fostira 2020, Dorling 2021, Toss 2021); This variant is associated with the following publications: (PMID: 34426522, 33471991, 22419737, 19782031, 30851065, 33919281, 26845104, 31300551)
Invitae	RCV000459747	SCV000550501	uncertain significance	Familial cancer of breast	2024-01-28	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 183 of the CHEK2 protein (p.Leu183Phe). This variant is present in population databases (rs745646057, gnomAD 0.003%). This missense change has been observed in individual(s) with breast cancer and/or colorectal cancer (PMID: 26845104, 31300551, 32658311, 33919281, 33925588). ClinVar contains an entry for this variant (Variation ID: 184928). 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 affects 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	RCV000459747	SCV000785293	uncertain significance	Familial cancer of breast	2017-06-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164270	SCV000903187	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 183 of the CHEK2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant has been determined to cause loss of CHEK2 function in DNA damage repair assay in yeast (PMID: 30851065). The p.Leu183 residue is located in the region between the kinase and FHA domains and may destabilize the protein or interfere with proper folding (PMID: 30851065). This variant has been reported in over ten individuals affected with breast cancer, including at least seven probands with early-onset of disease (PMID: 30851065, 31300551, 32658311, 33919281, 33925588; Color internal data). This variant has also been observed in two individuals affected with colorectal cancer (PMID: 32658311) and in two unaffected individuals having family history of colorectal cancer in the first-degree relatives (PMID: 26845104). This variant has been identified in 3/251416 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV000221179	SCV001245715	likely pathogenic	not provided	2019-10-01	criteria provided, single submitter	clinical testing
MGZ Medical Genetics Center	RCV000459747	SCV002579413	likely pathogenic	Familial cancer of breast	2021-09-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000221179	SCV003802790	likely pathogenic	not provided	2022-08-18	criteria provided, single submitter	clinical testing	The CHEK2 c.549G>C (p.Leu183Phe) missense variant results in the substitution of leucine at amino acid position 183 with phenylalanine. Across a selection of the available literature, this variant, which has been described as a founder variant in the Greek population (PMID: 33925588), has been identified in a heterozygous state in at least 14 unrelated individuals with breast cancer or colorectal cancer (PMID: 30851065; PMID: 31300551; PMID: 32658311; PMID: 33919281). The c.549G>C variant was also reported in a single control (PMID: 32658311). The highest frequency of this allele in the Genome Aggregation Database is 0.000026 in the European (non-Finnish) population (version 2.1.1). Functional characterization of the variant in yeast showed diminished cell growth, which suggests a damaging impact (PMID: 30851065). In addition, a different missense change at the same amino acid residue, c.548T>C (p.Leu183Ser), has been reported in individuals with breast cancer (PMID: 30851065). Based on the available evidence, the c.549G>C (p.Leu183Phe) variant is classified as likely pathogenic for CHEK2-related heredity cancer predisposition.
Myriad Genetics, Inc.	RCV000459747	SCV004020125	uncertain significance	Familial cancer of breast	2023-03-08	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003390866	SCV004119140	uncertain significance	CHEK2-related condition	2023-04-05	criteria provided, single submitter	clinical testing	The CHEK2 c.549G>C variant is predicted to result in the amino acid substitution p.Leu183Phe. This variant has been reported in individuals with breast cancer and individuals with colorectal cancer (Table S1, Shirts et al. 2016. PubMed ID: 26845104; Table S2, Fostira et al. 2020. PubMed ID: 31300551; Table S6, Akcay et al. 2020. PubMed ID: 32658311; Figure 4b, Delimitsou et al. 2019. PubMed ID: 30851065; Table 2, Toss et al. 2021. PubMed ID: 33919281; Table 1, Apostolou et al. 2021. PubMed ID: 33925588). It has also been reported in controls from two cohort studies (Table S6, Akcay et al. 2020. PubMed ID: 32658311; Dataset 4, Kars et al. 2021. PubMed ID: 34426522). In vivo experimental studies using a yeast based assay suggest this variant impacts protein function (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 3 of ~251,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/22-29121008-C-G). It has conflicting interpretations of likely pathogenic and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/184928/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357576	SCV001553083	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Leu183Phe variant was identified in 1 of 3856 proband chromosomes (frequency: 0.0003) from individuals with hereditary breast and ovarian cancer and was not identified in 6720 control chromosomes from healthy individuals (Kleiblova 2019). The variant was identified dbSNP (rs745646057) as “with uncertain significance allele” and ClinVar (interpreted as "uncertain significance" by Invitae, Color and 4 others). The variant was identified in control databases in 3 of 246,218 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 3 of 111,676 chromosomes (freq: 0.00003), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Leu183 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.