Description
Variant summary: CHEK2 c.1427C>T (p.Thr476Met) results in a non-conservative amino acid change located in the Protein kinase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 238040 control chromosomes. The observed variant frequency is approximately the same as the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00031), strongly suggesting that the variant is benign. Additionally, this variant has been observed in 8 individuals who are reportedly cancer free at age 70 in the FLOSSIES database. In addition, co-occurrences with other pathogenic variants have been observed at our laboratory (BRCA2 c.8677C>T, p.Gln2893*; PMS2 c.2444C>T, p.Ser815Leu), providing additional supporting evidence for a benign role. c.1427C>T has been reported in the literature in individuals affected with a variety of cancers such as Breast, Ovarian, Colorectal, and Pancreatic cancers (example, Le Calvez-Kelm_2011, Angelova_2012, Susswein_2015, Hu_2016, Schuber_2019, Henn_2019, Bertelsen_2019, Lerner-Ellis_2019). For some of these cases multigenic panel screening was performed, however, in most cases, the co-occurrence information was not provided and segregation studies were not performed. In addition, Leedom_2016 reported similar frequencies for the variant in their affected (at risk) population of European descent (0.07%; 46/62392 chromosomes tested). This variant was identified in an individual who tested positive for a large deletion encompassing exon 9-15 of CHEK2 in trans in an internal specimen.These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in disruption of CHEK2 kinase activity in vitro and impairs DNA damage response in a yeast assay (example, Desrichard_2011; Roeb_2012, Delimitsou_2019), suggesting a deleterious outcome or at least a possible modifying role of the variant in carcinogenesis. The following publications have been ascertained in the context of this evaluation (PMID: 22862163, 31341520, 31398194, 27621404, 31263571, 35643632, 28944238, 30851065, 22114986, 15095295, 28495237, 30680046, 26483394, 29922827, 29368341, 21244692, 27751358, 31784482, 30128536, 28008555, 27443514, 22419737, 30426508, 26845104, 26681312, 26787654, 29945567, 28135145, Young_2016). Multiple clinical diagnostic laboratories and other submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments. Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the evidence outlined above, the variant was classified as uncertain significance until more definitive data becomes available.
| # | Sample | Method | Observation |
|---|
| Origin | Affected | Number tested | Tissue | Purpose | Method | Individuals | Allele frequency | Families | Co-occurrences |
|---|
| 1 | germline | unknown | not provided | not provided | not provided | | not provided | not provided | not provided | not provided |
