Submissions for variant NM_007194.4(CHEK2):c.1204G>A (p.Ala402Thr)

gnomAD frequency: 0.00001  dbSNP: rs758206293

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000226188	SCV000289655	uncertain significance	Familial cancer of breast	2023-12-27	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 402 of the CHEK2 protein (p.Ala402Thr). This variant is present in population databases (rs758206293, gnomAD 0.002%). 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: 240732). 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 threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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.
Ambry Genetics	RCV000571196	SCV000669241	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-01	criteria provided, single submitter	clinical testing	The p.A402T variant (also known as c.1204G>A), located in coding exon 10 of the CHEK2 gene, results from a G to A substitution at nucleotide position 1204. The alanine at codon 402 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000571196	SCV000905488	uncertain significance	Hereditary cancer-predisposing syndrome	2020-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with threonine at codon 402 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 reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250958 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001284138	SCV001469764	uncertain significance	not provided	2019-11-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001284138	SCV002563710	uncertain significance	not provided	2022-07-01	criteria provided, single submitter	clinical testing	CHEK2: PM2, BP1, BP4
Baylor Genetics	RCV000226188	SCV004217655	uncertain significance	Familial cancer of breast	2023-06-21	criteria provided, single submitter	clinical testing