Submissions for variant NM_007194.4(CHEK2):c.164C>T (p.Ser55Phe)

gnomAD frequency: 0.00004  dbSNP: rs765799649

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000466798	SCV000550562	uncertain significance	Familial cancer of breast	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 55 of the CHEK2 protein (p.Ser55Phe). This variant is present in population databases (rs765799649, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian, peritoneal or fallopian tube cancer (PMID: 22006311, 31871109). ClinVar contains an entry for this variant (Variation ID: 410069). 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 does not substantially affect CHEK2 function (PMID: 22006311). 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.
GeneDx	RCV000759772	SCV000566935	uncertain significance	not provided	2023-06-21	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; Published functional studies demonstrate DNA damage response similar to wildtype in a yeast-based assay (Walsh et al., 2011); Observed in at least one individual with ovarian/fallopian tube/primary peritoneal cancer and an individual undergoing hereditary cancer genetic testing who also harbored a frameshift BRCA2 variant (Walsh et al., 2011; Adedokun et al., 2020); This variant is associated with the following publications: (PMID: 22006311, 11733767, 22114986, 31871109, 32832836, 26580448)
Ambry Genetics	RCV000574842	SCV000666365	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-14	criteria provided, single submitter	clinical testing	The p.S55F variant (also known as c.164C>T), located in coding exon 1 of the CHEK2 gene, results from a C to T substitution at nucleotide position 164. The serine at codon 55 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This alteration has been identified in individuals diagnosed with breast and/or ovarian cancer (Walsh T et al. Proc Natl Acad Sci U S A, 2011 Nov;108:18032-7; Adedokun B et al. Cancer Epidemiol Biomarkers Prev, 2020 02;29:359-367). In addition, this variant was identified in a cohort of 3,579 African males diagnosed with prostate cancer who underwent multi-gene panel testing of 19 DNA repair and cancer predisposition genes (Matejcic M. JCO Precis Oncol . 2020 Jan;4:32-43). This variant has also been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with a high grade glioma (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759772	SCV000889326	uncertain significance	not provided	2018-04-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000574842	SCV001339935	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 55 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). A functional study has shown the mutant protein to exhibit near normal activity in a yeast-based DNA damage repair / complementation assay (PMID: 22006311). This variant has been reported in an individual affected with a carcinoma of ovarian, fallopian tube, or peritoneal origin in the literature (PMID: 22006311) and in an individual affected with breast cancer who also carried a pathogenic variant in the BRCA2 gene (PMID: 31871109). This variant has been identified in 2/251444 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.
Genetic Services Laboratory, University of Chicago	RCV001821281	SCV002067159	uncertain significance	not specified	2020-12-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000574842	SCV002537406	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-25	criteria provided, single submitter	curation
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003325201	SCV004031217	uncertain significance	Predisposition to cancer	2023-07-06	criteria provided, single submitter	clinical testing	The CHEK2 c.164C>T (p.Ser55Phe) missense change has a maximum subpopulation frequency of 0.012% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and a yeast-based assay has shown that this variant is able to complement DNA damage hypersensitivity comparable to wild-type CHEK2 (PMID: 22006311). This variant has been identified in an individual with breast cancer who also harbored a pathogenic variant in BRCA2 (PMID: 31871109). It has also been identified in at least one African male with prostate cancer (PMID: 32832836, 36898365) and one female with a reproductive tract cancer where the wild-type allele was not lost in the tumor (PMID: 22006311). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.