ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1008G>A (p.Gln336=)

gnomAD frequency: 0.00004  dbSNP: rs201544715
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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000399000 SCV000329280 uncertain significance not provided 2023-04-04 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Observed in individuals with a personal of breast cancer, one of whom also had a family history of breast cancer (Tung et al., 2015; Castillo-Guardiola et al., 2022); This variant is associated with the following publications: (PMID: 25186627, 35245693)
Invitae RCV000465362 SCV000550516 likely benign Familial cancer of breast 2024-01-26 criteria provided, single submitter clinical testing
Ambry Genetics RCV000573690 SCV000661700 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-31 criteria provided, single submitter clinical testing The c.1008G>A variant (also known as p.Q336Q), located in coding exon 8 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1008. This nucleotide substitution does not change the glutamine at codon 336. However, this change occurs in the last base pair of coding exon 8, which makes it likely to have some effect on normal mRNA splicing. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000573690 SCV000684545 uncertain significance Hereditary cancer-predisposing syndrome 2022-09-26 criteria provided, single submitter clinical testing This synonymous variant alters the conserved last c.G nucleotide of exon 9 of the CHEK2 gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing, although this prediction has not been confirmed in published RNA studies. This variant has been reported in an individual affected with breast cancer in the literature (PMID: 25186627). This variant has been identified in 3/251444 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000399000 SCV001134153 uncertain significance not provided 2020-09-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193088 SCV001361678 uncertain significance not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: CHEK2 c.1008G>A (p.Gln336Gln) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1008G>A has been reported in the literature in at-least one individual affected with Breast Cancer (Tung_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported at our laboratory (BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago RCV001193088 SCV002064984 uncertain significance not specified 2017-08-07 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000573690 SCV002537013 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-05 criteria provided, single submitter curation
Baylor Genetics RCV000465362 SCV004217561 uncertain significance Familial cancer of breast 2023-09-08 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000573690 SCV004228128 uncertain significance Hereditary cancer-predisposing syndrome 2023-09-21 criteria provided, single submitter clinical testing

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