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

gnomAD frequency: 0.00004  dbSNP: rs201544715

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000399000	SCV000329280	uncertain significance	not provided	2025-03-11	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with a personal history of breast or other cancers (PMID: 35245693, 25186627, 38061684, 34326862, 38075165); 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.; This variant is associated with the following publications: (PMID: 25186627, 35245693, 38061684, 38075165, 34326862, 35451682)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000465362	SCV000550516	likely benign	Familial cancer of breast	2025-01-29	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	2024-03-29	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