ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1024G>A (p.Gly342Ser) (rs730881705)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212444 SCV000211022 uncertain significance not provided 2019-07-25 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 18306035, 30851065)
Ambry Genetics RCV000160457 SCV000216850 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-13 criteria provided, single submitter clinical testing The p.G342S variant (also known as c.1024G>A), located in coding exon 9 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1024. The glycine at codon 342 is replaced by serine, an amino acid with similar properties. This alteration behaved as 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 RCV000230102 SCV000289639 uncertain significance Familial cancer of breast 2020-09-26 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 342 of the CHEK2 protein (p.Gly342Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is present in population databases (rs730881705, ExAC 0.009%). This variant has not been reported in the literature in individuals with CHEK2-related disease. ClinVar contains an entry for this variant (Variation ID: 182457). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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 Health, Inc RCV000160457 SCV000684548 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-29 criteria provided, single submitter clinical testing This missense variant replaces glycine with serine at codon 342 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). An experimental functional study has shown this variant to be neutral in a yeast based DNA damage repair assay (PMID: 30851065). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 16/251112 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.
Mendelics RCV000230102 SCV000839469 uncertain significance Familial cancer of breast 2018-07-02 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765617 SCV000896942 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Bone osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing

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