ClinVar Genomic variation as it relates to human health

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 356 of the CHEK2 protein (p.Ser356Leu). This variant is present in population databases (rs121908703, gnomAD 0.004%). This missense change has been observed in individual(s) with non-Hodgkin lymphoma, thyroid cancer, or breast cancer (PMID: 26506619, 29700698, 30303537). ClinVar contains an entry for this variant (Variation ID: 126907). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31050813, 31409080). 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.

The p.S356L variant (also known as c.1067C>T), located in coding exon 9 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1067. The serine at codon 356 is replaced by leucine, an amino acid with dissimilar properties. 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 alteration was identified in an individual diagnosed with breast and/or ovarian cancer (Aksoy F et al. Hum Hered, 2022 Jan;:). 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.

Published functional studies demonstrate DNA damage response comparable to wild type in a yeast-based assay as well as normal Chk2-autophosphorylation but intermediate/reduced kinase activity against KAP1 in human-cell based studies (PMID: 30851065, 31050813, 37449874); Observed in individuals with a personal and/or family history of breast and other cancers, but also observed in controls (PMID: 29700698, 30303537, 31050813, 34991090, 36315097); 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; This variant is associated with the following publications: (PMID: 26506619, 29700698, 34426522, 31050813, 30303537, 34991090, 34565017, 30851065, 37449874, 36315097, 19782031, 22419737)

Variant summary: The CHEK2 c.1067C>T (p.Ser356Leu) variant involves the alteration of a conserved nucleotide and is predicted to be damaging by 4/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant was found in 4/215270 control chromosomes (gnomAD), predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000036 (4/111556). This frequency is about 1.3 times the estimated maximal expected allele frequency of an LFS-causing CHEK2 variant (0.0000284), suggesting this may be a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. However, there are no other supporting evidences. This variant has been reported in one patient with non-Hodgkin Lymphoma (Havranek_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is classified as Variant of Unknown Significance.

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.

This missense variant replaces serine with leucine at codon 356 of the CHEK2 protein. Computational prediction tools and conservation analyses suggest that this variant may not impact protein structure and function. Functional studies have provide inconclusive results regarding this variant. The variant did not show functional deficit in a yeast DNA repair assay (PMID 30851065) but demonstrated intermediate functional impact in a kinase assay (PMID 31050813). This variant has been reported in 2 individuals with breast cancer (PMID: 30303537), an individual affected with non-Hodgkin lymphoma (PMID 26506619), and a patient with thyroid carcinoma (PMID 29700698) in the literature. This variant has been identified in 4/251254 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.

The CHEK2 c.1067C>T variant is predicted to result in the amino acid substitution p.Ser356Leu. This variant has been reported as a germline variant in an individual with Non-Hodgkin lymphoma (NHL) (Havranek et al. 2015. PubMed ID: 26506619) and in individuals with familial breast cancer (Supplementary Table S3, Girard et al. 2018. PubMed ID: 30303537). This variant has also been reported in the control population in an study of individuals with breast and ovarian cancer (Table 1, Kleiblova et al. 2019. PubMed ID: 31050813). A study analyzing in silico prediction tools and a yeast functional assay reported conflicting results for this variant, with in silico suggesting it is possibly damaging and in vivo results finding it benign (Table 1, Delimitsou et al. 2019. PubMed ID: 30851065). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted with uncertain significance in ClinVar by several outside laboratories (https://www.ncbi.nlm.nih.gov/clinvar/variation/126907/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

The CHEK2 p.Ser356Leu variant was identified in 1 of 680 proband chromosomes (frequency: 0.002) from individuals or families with Non-Hodgkin Lymphoma and was not identified in 890 control chromosomes from healthy individuals (Havranek 2015). The variant was also identified in dbSNP (ID: rs121908703) as "With Uncertain significance allele", in ClinVar (classified as uncertain significance by Ambry Geneics, Invitae, Color Genomics), Cosmic (1x in urinary tract tumor), and in MutDB. The variant was not identified in Zhejiang University database. The variant was identified in control databases in 4 of 246052 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in European population in 4 of 111556 chromosomes (freq: 0.00004), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ser356 residue is conserved in mammals but not in more distantly related 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, 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.