Submissions for variant NM_000051.4(ATM):c.7000T>C (p.Tyr2334His)

dbSNP: rs1064793312

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000479256	SCV000565739	uncertain significance	not provided	2016-07-26	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.7000T>C at the cDNA level, p.Tyr2334His (Y2334H) at the protein level, and results in the change of a Tyrosine to a Histidine (TAC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr2334His was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Tyrosine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr2334His occurs at a position that is not conserved and is located in the within FAT domain (Tavtigian 2009, Stracker 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether ATM Tyr2334His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000581847	SCV000687748	uncertain significance	Hereditary cancer-predisposing syndrome	2019-04-11	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001064965	SCV001229902	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with histidine, which is basic and polar, at codon 2334 of the ATM protein (p.Tyr2334His). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 418584). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The histidine 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	RCV000581847	SCV002668127	uncertain significance	Hereditary cancer-predisposing syndrome	2022-08-30	criteria provided, single submitter	clinical testing	The p.Y2334H variant (also known as c.7000T>C), located in coding exon 47 of the ATM gene, results from a T to C substitution at nucleotide position 7000. The tyrosine at codon 2334 is replaced by histidine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species; however, histidine is the reference amino acid in other 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.
Baylor Genetics	RCV003470529	SCV004210245	uncertain significance	Familial cancer of breast	2023-06-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004586728	SCV005077338	uncertain significance	not specified	2024-04-07	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551580	SCV004745627	uncertain significance	ATM-related disorder	2023-12-27	no assertion criteria provided	clinical testing	The ATM c.7000T>C variant is predicted to result in the amino acid substitution p.Tyr2334His. To our knowledge, this variant has not been reported in the literature or in a large population database, indicating this variant is rare. This variant is interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/418584/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.