Submissions for variant NM_007194.4(CHEK2):c.38A>G (p.His13Arg)

dbSNP: rs1064793324

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480755	SCV000565808	uncertain significance	not provided	2015-03-04	criteria provided, single submitter	clinical testing	This variant is denoted CHEK2 c.38A>G at the cDNA level, p.His13Arg (H13R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). Although this variant was observed in a patient with bilateral breast cancer and a uterine sarcoma, functional assays demonstrated the resultant protein's properties as comparable to wild-type (Manoukian 2011). CHEK2 His13Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. CHEK2 His13Arg occurs at a position that is conserved across mammals, with Arginine being the naturally occurring amino acid at this position in two species, and is not located in a known functional domain (Desrichard 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether CHEK2 His13Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000547774	SCV000633177	uncertain significance	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 13 of the CHEK2 protein (p.His13Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with breast cancer and/or sarcoma (PMID: 21562711). ClinVar contains an entry for this variant (Variation ID: 418613). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The arginine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change does not substantially affect CHEK2 function (PMID: 21562711). 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	RCV000775780	SCV000910227	uncertain significance	Hereditary cancer-predisposing syndrome	2019-08-07	criteria provided, single submitter	clinical testing	This missense variant replaces histidine with arginine at codon 13 of the CHEK2 protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. This variant has been reported in one individual affected with personal history and family history of breast cancer and adenosarcoma (PMID: 21562711). Functional studies have shown that the variant does not affect catalytic activity or stability of the CHEK2 protein (PMID: 21562711). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). 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.
Ambry Genetics	RCV000775780	SCV002620692	likely benign	Hereditary cancer-predisposing syndrome	2015-11-25	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.