ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1153T>C (p.Cys385Arg)

gnomAD frequency: 0.00001  dbSNP: rs587782817
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132390 SCV000187482 uncertain significance Hereditary cancer-predisposing syndrome 2022-11-18 criteria provided, single submitter clinical testing The p.C385R variant (also known as c.1153T>C), located in coding exon 10 of the CHEK2 gene, results from a T to C substitution at nucleotide position 1153. The cysteine at codon 385 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 04;7:1349-1358). 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, 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.
Invitae RCV000205294 SCV000261286 uncertain significance Familial cancer of breast 2024-01-24 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 385 of the CHEK2 protein (p.Cys385Arg). This variant is present in population databases (rs587782817, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CHEK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 142917). 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.
GeneDx RCV000216008 SCV000279292 uncertain significance not provided 2023-04-05 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 a BRCA1/2-negative individual with breast cancer (Hauke et al., 2018); Published functional studies demonstrate a damaging effect: loss of CHEK2-mediated DNA damage response (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 31398194, 29522266, 22419737, 19782031, 30851065, 32826389)
Counsyl RCV000205294 SCV000785651 uncertain significance Familial cancer of breast 2017-10-19 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000132390 SCV002053133 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-08 criteria provided, single submitter clinical testing This missense variant replaces cysteine with arginine at codon 385 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, 31398194). A functional study has demonstrated this variant to be damaging in a yeast based DNA damage response assay (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/282412 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.
Myriad Genetics, Inc. RCV000205294 SCV004020119 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.
Preventiongenetics, part of Exact Sciences RCV003398774 SCV004119100 uncertain significance CHEK2-related condition 2023-01-31 criteria provided, single submitter clinical testing The CHEK2 c.1153T>C variant is predicted to result in the amino acid substitution p.Cys385Arg. To our knowledge, this variant has not been reported in the literature in any patients affected with CHEK2-related conditions. It has, however, been reported as a damaging variant in a yeast-based functional assay (Delimitsou et al. 2019. PubMed I: 30851065). This variant is reported in 0.0040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-29091804-A-G). It is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/142917/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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