Submissions for variant NM_000051.4(ATM):c.2723T>C (p.Val908Ala)

dbSNP: rs754738085

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235339	SCV000294077	uncertain significance	not provided	2016-03-09	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.2723T>C at the cDNA level, p.Val908Ala (V908A) at the protein level, and results in the change of a Valine to an Alanine (GTA>GCA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val908Ala 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 Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. ATM Val908Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species and is not located in a known functional domain (Tavtigian 2009, Stracker 2013). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Val908Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000554420	SCV000622353	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 908 of the ATM protein (p.Val908Ala). 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: 246496). 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. 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	RCV000581765	SCV000687413	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces valine with alanine at codon 908 of the ATM 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. In a large international case-control study, this variant was reported in 2/60464 breast cancer cases and 2/53459 controls (OR=0.884, 95%CI 0.125 to 6.277, p-value=1; PMID: 33471991). This variant has not been identified 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.
Ambry Genetics	RCV000581765	SCV001177359	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing	The p.V908A variant (also known as c.2723T>C), located in coding exon 17 of the ATM gene, results from a T to C substitution at nucleotide position 2723. The valine at codon 908 is replaced by alanine, 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 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.
Fulgent Genetics, Fulgent Genetics	RCV002487101	SCV002785185	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-08-04	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV004567792	SCV005057111	uncertain significance	Familial cancer of breast	2023-12-30	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000554420	SCV001452050	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000235339	SCV001979737	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000235339	SCV001980121	likely benign	not provided		no assertion criteria provided	clinical testing