Submissions for variant NM_007194.4(CHEK2):c.688G>T (p.Ala230Ser)

gnomAD frequency: 0.00006  dbSNP: rs748636216

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166779	SCV000217592	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-27	criteria provided, single submitter	clinical testing	The p.A230S variant (also known as c.688G>T), located in coding exon 5 of the CHEK2 gene, results from a G to T substitution at nucleotide position 688. The alanine at codon 230 is replaced by serine, an amino acid with similar properties. This alteration has been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This alteration was also identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and in 0/1199 general population controls (Girard E et al. Int. J. Cancer, 2019 04;144:1962-1974). In another matched control study, this alteration was identified in 0/1313 female probands with early-onset breast cancer and 1/1123 healthy matched controls (Le Calvez-Kelm F et al. Breast Cancer Res., 2011 Jan;13:R6). Another study identified this alteration in 0/1928 breast and/or ovarian cancer patients and 1/3360 population-matched controls. In a functional assay included in this study, results for this alteration were indeterminate (Kleiblova P et al. Int. J. Cancer, 2019 10;145:1782-1797). 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200524	SCV000254949	uncertain significance	Familial cancer of breast	2024-12-11	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 230 of the CHEK2 protein (p.Ala230Ser). This variant is present in population databases (rs748636216, gnomAD 0.004%). This missense change has been observed in individual(s) with breast cancer (PMID: 30303537, 35475445). ClinVar contains an entry for this variant (Variation ID: 187091). 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 are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065, 31050813). 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.
GeneDx	RCV000657065	SCV000568010	uncertain significance	not provided	2024-03-10	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; Observed in individuals with breast or colorectal cancer, but also in unaffected controls (PMID: 21244692, 26787654, 28779002, 30303537, 35475445); This variant is associated with the following publications: (PMID: 21244692, 26787654, 30303537, 28779002, 30851065, 35475445, 22419737, 19782031, 31050813)
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000657065	SCV000601177	uncertain significance	not provided	2023-09-29	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000166779	SCV000684680	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-04	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with serine at codon 230 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 shown this variant to have neutral to intermediate effects on CHEK2 function in vitro kinase assays and yeast DNA damage repair assays (PMID 30851065, 31050813). This variant has been reported in an individual suspected of having Lynch syndrome (PMID: 35475445). This variant has been identified in 8/282656 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	RCV000200524	SCV000785835	uncertain significance	Familial cancer of breast	2017-12-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV004556758	SCV001308838	uncertain significance	CHEK2-related cancer predisposition	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000200524	SCV004015284	uncertain significance	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing	This sequence change replaces alanine with serine at codon 230 of the CHEK2 protein (p.Ala230Ser). This variant has been observed in individual(s) with breast cancer (PMID: 30303537). ClinVar contains an entry for this variant (Variation ID: 187091) with 8 submissions, all of which describe it as of uncertain significance. This variant has been reported to have conflicting or insufficient data to determine the effect on CHEK2 protein function (PMID: 30851065, 31050813). In-silico predictions show benign computational verdict based on 7 benign predictions from BayesDel_addAF, DEOGEN2, EIGEN, M-CAP, MVP, MutationAssessor and PrimateAI vs 5 pathogenic predictions from DANN, FATHMM-MKL, LIST-S2, MutationTaster and SIFT and the position is not strongly conserved. Therefore, it has been classified as a Variant of Uncertain Significance.
Myriad Genetics, Inc.	RCV000200524	SCV004020137	uncertain significance	Familial cancer of breast	2023-03-08	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	RCV000200524	SCV004217513	uncertain significance	Familial cancer of breast	2024-03-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357581	SCV001553090	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The CHEK2 p.Ala230Ser variant was identified in 1 of 30254 proband chromosomes (frequency: 0.00003) from individuals or families with breast cancer and was present in 1 of 2218 control chromosomes (frequency: 0.0005) from healthy individuals (Decker 2017, Le Calvez-Kelm 2011). The variant was also identified in dbSNP (ID: rs748636216) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and four other submitters). The variant was identified in control databases in 8 of 277002 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 23996 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 1 of 34418 chromosomes (freq: 0.00003), and European in 5 of 126642 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Ala230 residue is conserved in mammals but not in more distantly related organisms and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.