Submissions for variant NM_007194.4(CHEK2):c.915A>C (p.Glu305Asp)

gnomAD frequency: 0.00001  dbSNP: rs587780191

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000116032	SCV000149941	uncertain significance	not provided	2024-02-11	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 demonstrate KAP1 phosphorylation and CHK2 auto-phosphorylation similar to wildtype (PMID: 37449874); Identified in individuals with breast or endometrial cancer but also in unaffected controls (PMID: 27443514, 28779002, 33471991, 37449874); This variant is associated with the following publications: (PMID: 27443514, 33099347, 33471991, 19782031, 22419737, 28779002, 37449874)
Ambry Genetics	RCV000213975	SCV000275407	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-13	criteria provided, single submitter	clinical testing	The p.E305D variant (also known as c.915A>C), located in coding exon 8 of the CHEK2 gene, results from an A to C substitution at nucleotide position 915. The glutamic acid at codon 305 is replaced by aspartic acid, an amino acid with highly similar properties. This alteration was reported as functional in a study assessing CHEK2-complementation through quantification of KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells (Stolarova L et al. Clin Cancer Res, 2023 Aug;29:3037-3050). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000473787	SCV000550463	uncertain significance	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 305 of the CHEK2 protein (p.Glu305Asp). This variant is present in population databases (rs587780191, gnomAD 0.003%). This missense change has been observed in individual(s) with endometrial cancer (PMID: 27443514). ClinVar contains an entry for this variant (Variation ID: 128088). 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.
Color Diagnostics, LLC DBA Color Health	RCV000213975	SCV000684698	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-19	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 305 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast and endometrial cancer in the literature (PMID: 27443514, 28779002) . In a large breast cancer case-control study, this variant has been observed in 3/60466 cases and 2/53461 unaffected controls (OR=1.326; 95%CI 0.222 to 7.938); p-value=1; Leiden Open Variation Database DB-ID CHEK2_000403) (PMID: 33471991). This variant has been identified in 5/282456 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001251264	SCV001426782	uncertain significance	not specified	2020-07-10	criteria provided, single submitter	clinical testing	Variant summary: CHEK2 c.915A>C (p.Glu305Asp) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251072 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.915A>C has been reported in the literature as a VUS in at-least one individual affected with Endometrial cancer (Ring_2016). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. 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	RCV001251264	SCV002068112	uncertain significance	not specified	2020-05-01	criteria provided, single submitter	clinical testing	DNA sequence analysis of the CHEK2 gene demonstrated a sequence change, c.915A>C, in exon 9 that results in an amino acid change, p.Glu305Asp. This sequence change does not appear to have been previously described in patients with CHEK2 -related disorders and has been described in the gnomAD database with a low population frequency of 0.0018% (rs587780191). The p.Glu305Asp change affects a moderately conserved amino acid residue located in a domain of the CHEK2 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu305Asp substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu305Asp change remains unknown at this time.
Sema4, Sema4	RCV000213975	SCV002537653	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	curation
Baylor Genetics	RCV000473787	SCV004217498	uncertain significance	Familial cancer of breast	2024-02-21	criteria provided, single submitter	clinical testing