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

gnomAD frequency: 0.00001  dbSNP: rs730881705

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212444	SCV000211022	uncertain significance	not provided	2023-05-04	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 patient with breast cancer (Guindalini et al., 2022); Variant considered functional in a yeast-based growth rate assay (Delimitsou et al., 2019); This variant is associated with the following publications: (PMID: 18306035, 22419737, 19782031, 35264596, 30851065)
Ambry Genetics	RCV000160457	SCV000216850	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-26	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	2023-12-18	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 342 of the CHEK2 protein (p.Gly342Ser). This variant is present in population databases (rs730881705, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer (PMID: 35264596). ClinVar contains an entry for this variant (Variation ID: 182457). 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.
Color Diagnostics, LLC DBA Color Health	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
Baylor Genetics	RCV000230102	SCV004217635	uncertain significance	Familial cancer of breast	2023-07-13	criteria provided, single submitter	clinical testing