Submissions for variant NM_007194.4(CHEK2):c.1117A>G (p.Lys373Glu)

dbSNP: rs74751600

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568436	SCV000665253	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-29	criteria provided, single submitter	clinical testing	The p.K373E variant (also known as c.1117A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1117. The lysine at codon 373 is replaced by glutamic acid, an amino acid with similar properties. This alteration was identified in 4 individuals of Chinese descent with triple negative breast cancer, but was not identified in the Asian control population in this study (Liu et al. Cancer Med. 2017 Mar;6(3):547-554). This alteration has been reported as a somatic alteration and was shown to result in disrupted CHK2 autophosphorylation and disrupted CHK2 kinase activity (Higashiguchi M et al. FEBS Lett., 2016 Oct). This alteration has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and 0.0000 in 11241 female controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). Based on data from gnomAD, the frequency for this variant is above the maximum credible frequency for a disease-causing variant in this gene based on internally established thresholds (Karczewski et al. Nature. 2020 May;581(7809):434-443; Whiffin et al. Genet Med. 2017 10;19:1151-1158). Of note, this alteration is also described in the literature as c.1246A>G using the isoform NM_001005735.1. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Mendelics	RCV000709596	SCV000839466	uncertain significance	Familial cancer of breast	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV000709596	SCV000943250	uncertain significance	Familial cancer of breast	2023-06-30	criteria provided, single submitter	clinical testing	This missense change has been observed in individual(s) with breast cancer (PMID: 28135048). This variant is also known as as c.1246A>G (p.Lys416Glu). ClinVar contains an entry for this variant (Variation ID: 481100). 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. Experimental studies have shown that this missense change affects CHEK2 function (PMID: 27716909). 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. This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 373 of the CHEK2 protein (p.Lys373Glu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database.
Color Diagnostics, LLC DBA Color Health	RCV000568436	SCV001344062	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-01	criteria provided, single submitter	clinical testing	This missense variant replaces lysine with glutamic acid at codon 373 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 impacts CHEK2 function in autophosphorylation and phosphorylation of KAP1 (PMID: 27716909). This variant has been reported in at least 5 individuals affected with breast cancer (PMID: 28135048, 30287823) and in a breast cancer case-control meta-analysis in 20/73048 female BC cases and 3/88658 unaffected controls with OR 10.8 (95% CI 3.20-56.75) (PMID: 37449874). This variant has not been identified 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.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000709596	SCV001429429	uncertain significance	Familial cancer of breast	2018-10-24	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320474	SCV004024621	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing