Submissions for variant NM_007194.4(CHEK2):c.322T>C (p.Cys108Arg)

dbSNP: rs730881681

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212413	SCV000210957	uncertain significance	not provided	2016-08-05	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.322T>C at the cDNA level, p.Cys108Arg (C108R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. CHEK2 Cys108Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Cys108Arg occurs at a position that is conserved across species and is located in 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 Cys108Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000160423	SCV000217985	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-22	criteria provided, single submitter	clinical testing	The p.C108R variant (also known as c.322T>C), located in coding exon 2 of the CHEK2 gene, results from a T to C substitution at nucleotide position 322. The cysteine at codon 108 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has 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 was also detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). Additionally, 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, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000198019	SCV000254939	uncertain significance	Familial cancer of breast	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 108 of the CHEK2 protein (p.Cys108Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of CHEK2-related conditions (PMID: 32660107, 34326862). ClinVar contains an entry for this variant (Variation ID: 182424). 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	RCV000198019	SCV000785065	uncertain significance	Familial cancer of breast	2017-04-04	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160423	SCV000913602	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-12	criteria provided, single submitter	clinical testing	This missense variant replaces cysteine with arginine at codon 108 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). A functional study has shown this variant to be damaging in DNA damage response assay in yeast (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified 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.
Division of Medical Genetics, University of Washington	RCV000198019	SCV001424801	uncertain significance	Familial cancer of breast	2019-08-09	criteria provided, single submitter	clinical testing	To our knowledge, this sequence variant has not been previously reported in the literature. This variant is not present in population databases https://gnomad.broadinstitute.org/. In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212413	SCV002009503	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000198019	SCV003920999	uncertain significance	Familial cancer of breast	2023-03-13	criteria provided, single submitter	clinical testing	_x000D_ Criteria applied: PM2_SUP, PP3
Myriad Genetics, Inc.	RCV000198019	SCV004020147	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.