ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.549G>C (p.Leu183Phe) (rs745646057)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164270 SCV000214895 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-12 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 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 2015-12-03 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.549G>C at the cDNA level, p.Leu183Phe (L183F) at the protein level, and results in the change of a Leucine to a Phenylalanine (TTG>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Leu183Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. CHEK2 Leu183Phe occurs at a position that is conserved across species and is located within the FHA domain (Roeb 2012). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether CHEK2 Leu183Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000459747 SCV000550501 uncertain significance Familial cancer of breast 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 183 of the CHEK2 protein (p.Leu183Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs745646057, ExAC 0.001%). This variant has been observed in individual(s) with breast cancer (PMID: 31300551). ClinVar contains an entry for this variant (Variation ID: 184928). This variant has been reported to affect CHEK2 protein 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 Health, Inc RCV000164270 SCV000903187 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-14 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). A structural study has indicated that p.Leu183 residue is located in the interspace between kinase and FHA domains and this variant 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; 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 Praxis fuer Humangenetik Tuebingen RCV000221179 SCV001245715 likely pathogenic not provided 2019-10-01 criteria provided, single submitter clinical testing
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.

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