Submissions for variant NM_007194.4(CHEK2):c.1201A>G (p.Thr401Ala)

gnomAD frequency: 0.00001  dbSNP: rs121908704

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000114764	SCV000149897	uncertain significance	not provided	2020-04-01	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with non-Hodgkin lymphoma (Havranek 2015); Published functional studies are inconclusive: intermediate DNA damage response in in vivo yeast-based assays (Delimitsou 2019); This variant is associated with the following publications: (PMID: 26506619, 30851065)
Ambry Genetics	RCV000115988	SCV000216637	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-02	criteria provided, single submitter	clinical testing	The p.T401A variant (also known as c.1201A>G), located in coding exon 10 of the CHEK2 gene, results from an A to G substitution at nucleotide position 1201. The threonine at codon 401 is replaced by alanine, an amino acid with similar properties. This alteration behaved as semi-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 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.
Invitae	RCV000232135	SCV000289654	uncertain significance	Familial cancer of breast	2024-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 401 of the CHEK2 protein (p.Thr401Ala). This variant is present in population databases (rs121908704, gnomAD 0.004%). This missense change has been observed in individual(s) with non-Hodgkin lymphoma, and breast cancer (PMID: 26506619, 30851065). ClinVar contains an entry for this variant (Variation ID: 126908). 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. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CHEK2 function (PMID: 30851065). 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	RCV000115988	SCV000689639	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-12	criteria provided, single submitter	clinical testing	This missense variant replaces threonine with alanine at codon 401 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). A functional study has shown this variant to result in partial loss of CHEK2 function (PMID: 30851065). This variant has been reported in an individual affected with non-Hodgkin lymphoma (PMID: 26506619). This variant has been identified in 4/250994 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	RCV000232135	SCV000785056	uncertain significance	Familial cancer of breast	2017-03-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000232135	SCV004020213	uncertain significance	Familial cancer of breast	2023-03-09	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	RCV000232135	SCV004217537	uncertain significance	Familial cancer of breast	2023-09-25	criteria provided, single submitter	clinical testing
Institute. of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University in Prague	RCV000114764	SCV000148659	not provided	not provided		no assertion provided	not provided