Submissions for variant NM_007194.4(CHEK2):c.1130A>G (p.Glu377Gly)

gnomAD frequency: 0.00003  dbSNP: rs560973106

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212450	SCV000149892	uncertain significance	not provided	2023-04-12	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; Published functional studies suggest no damaging effect: growth rate similar to wild type in yeast-based assays and no effect on splicing (Casadei et al., 2019; Delimitsou et al., 2019); Observed in individuals with a personal and/or family history of breast and other cancers, as well as in healthy controls (Hauke et al., 2018; Casadei et al., 2019; Lovejoy et al., 2018; Weitzel et al., 2019); This variant is associated with the following publications: (PMID: 29522266, 30851065, 31843900, 22419737, 19782031, Lovejoy2018, 31206626)
Ambry Genetics	RCV000115983	SCV000217474	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-25	criteria provided, single submitter	clinical testing	The p.E377G variant (also known as c.1130A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1130. The glutamic acid at codon 377 is replaced by glycine, 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 alteration was detected in 0X/1054 Hispanic BRCA1/2-negative probands with hereditary breast cancer and 1/1189 controls (Weitzel JN et al. Cancer, 2019 Aug;125:2829-2836). This alteration was detected in 1/5589 German BRCA1/2-negative probands with breast cancer (Hauke J et al. Cancer Med, 2018 Apr;7:1349-1358). 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.
Color Diagnostics, LLC DBA Color Health	RCV000115983	SCV000292196	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-29	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 377 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). Functional studies have reported that this variant has a neutral impact on protein function in a yeast complementation assay (PMID: 30851065) and does not affect RNA splicing (PMID: 31843900). This variant has been reported in two individuals affected with breast cancer (PMID: 29522266; Lovejoy et al., Austin J Cancer Clin Res. 2018; 5(1): 1082), as well as in an individual age 70 years or older lacking personal history of cancer (https://whi.color.com/variant/22-29091827-T-C). This variant has been identified in 7/250492 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.
Counsyl	RCV000412249	SCV000489162	uncertain significance	Familial cancer of breast	2016-08-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000412249	SCV000633099	uncertain significance	Familial cancer of breast	2023-12-15	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 377 of the CHEK2 protein (p.Glu377Gly). This variant is present in population databases (rs560973106, gnomAD 0.01%). 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: 128045). 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 tolerated. 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.
Sema4, Sema4	RCV000115983	SCV002537024	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-19	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149808	SCV003838124	uncertain significance	Breast and/or ovarian cancer	2022-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001171425	SCV003845107	uncertain significance	not specified	2023-02-03	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.1130A>G (p.Glu377Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250492 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1130A>G has been reported in the literature without strong evidence for causality (Casadei_2019). Experimental studies have reported the variant to have no impact on function or splicing (Delimitsou_2019, Casadei_2019). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Six submitters classified the variant as VUS while one classified as benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000412249	SCV004020220	uncertain significance	Familial cancer of breast	2023-03-09	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.
Baylor Genetics	RCV000412249	SCV004217514	uncertain significance	Familial cancer of breast	2024-03-21	criteria provided, single submitter	clinical testing
King Laboratory, University of Washington	RCV001171425	SCV001251333	benign	not specified	2019-09-01	no assertion criteria provided	research