Submissions for variant NM_007194.4(CHEK2):c.1603C>T (p.Arg535Cys)

dbSNP: rs576248104

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160442	SCV000211001	uncertain significance	not provided	2017-07-17	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.1603C>T at the cDNA level, p.Arg535Cys (R535C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). Using alternate nomenclature, this variant would be defined as CHEK2 1732C>T (R578C). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. CHEK2 Arg535Cys occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether CHEK2 Arg535Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000218861	SCV000278039	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-28	criteria provided, single submitter	clinical testing	The p.R535C variant (also known as c.1603C>T), located in coding exon 14 of the CHEK2 gene, results from a C to T substitution at nucleotide position 1603. The arginine at codon 535 is replaced by cysteine, an amino acid with highly dissimilar properties. This variant was detected in 1/333 Polish patients with ovarian cancer (Koczkowska M et al. Cancers (Basel), 2018 Nov;10:). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000536005	SCV000633153	uncertain significance	Familial cancer of breast	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 535 of the CHEK2 protein (p.Arg535Cys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with ovarian cancer (PMID: 30441849). ClinVar contains an entry for this variant (Variation ID: 182442). 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 tolerated. 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.
Color Diagnostics, LLC DBA Color Health	RCV000218861	SCV000913567	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 535 of the CHEK2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with ovarian cancer in the literature (PMID: 30441849). This variant has been identified in 4/233674 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001824646	SCV002074163	uncertain significance	not specified	2022-01-09	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1603C>T (p.Arg535Cys) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 233674 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1603C>T has been reported in the literature in individuals affected with Breast and Ovarian Cancer (example: Koczkowska_2018, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed this variant since 2014: all submitters classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sema4, Sema4	RCV000218861	SCV002537403	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-12	criteria provided, single submitter	curation
Baylor Genetics	RCV000536005	SCV004217575	uncertain significance	Familial cancer of breast	2023-09-04	criteria provided, single submitter	clinical testing