Submissions for variant NM_007194.4(CHEK2):c.158C>G (p.Ser53Cys)

gnomAD frequency: 0.00001  dbSNP: rs753204096

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214765	SCV000273484	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	The p.S53C variant (also known as c.158C>G), located in coding exon 1 of the CHEK2 gene, results from a C to G substitution at nucleotide position 158. The serine at codon 53 is replaced by cysteine, an amino acid with dissimilar properties. This variant was identified in an individual from Trinidad and Tobago who was diagnosed with breast cancer at age 29 (George SHL et al. JAMA Netw Open, 2021 Mar;4:e210307). 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.
GeneDx	RCV000585913	SCV000570865	uncertain significance	not provided	2022-12-14	criteria provided, single submitter	clinical testing	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; Observed in an individual with breast or ovarian cancer (George et al., 2021); This variant is associated with the following publications: (PMID: 22114986, 11733767, 33646313)
Color Diagnostics, LLC DBA Color Health	RCV000214765	SCV000684612	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-16	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 53 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 13/251428 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	RCV001175354	SCV000698789	uncertain significance	not specified	2019-12-10	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.158C>G (p.Ser53Cys) results in a non-conservative amino acid change in 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 5.2e-05 in 251428 control chromosomes, predominantly at a frequency of 0.00042 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.34 fold of the estimated maximal expected allele frequency for a pathogenic variant in CHEK2 causing Breast Cancer phenotype (0.00031), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. However, this data is not completely reliable due to the known pseudogene in CHEK2.To our knowledge, no occurrence of c.158C>G in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS possibly-benign.
Invitae	RCV000696869	SCV000825449	uncertain significance	Familial cancer of breast	2024-01-21	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 53 of the CHEK2 protein (p.Ser53Cys). This variant is present in population databases (rs753204096, gnomAD 0.04%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with breast cancer (PMID: 33646313). ClinVar contains an entry for this variant (Variation ID: 230067). 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. 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.