Submissions for variant NM_000051.4(ATM):c.4516G>A (p.Val1506Met)

dbSNP: rs760542469

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196341	SCV000254111	uncertain significance	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 1506 of the ATM protein (p.Val1506Met). This variant is present in population databases (no rsID available, gnomAD 0.003%). 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: 216218). 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 disruptive. 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.
GeneDx	RCV000236242	SCV000293374	uncertain significance	not provided	2015-11-04	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4516G>A at the cDNA level, p.Val1506Met (V1506M) at the protein level, and results in the change of a Valine to a Methionine (GTG>ATG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Val1506Met 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 Methionine share similar properties, this is considered a conservative amino acid substitution. ATM Val1506Met occurs at a position that is conserved across species and is not located in a known functional 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 Val1506Met is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV001022617	SCV001184375	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-13	criteria provided, single submitter	clinical testing	The p.V1506M variant (also known as c.4516G>A), located in coding exon 29 of the ATM gene, results from a G to A substitution at nucleotide position 4516. The valine at codon 1506 is replaced by methionine, an amino acid with highly similar properties. This variant was reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004567417	SCV005057107	uncertain significance	Familial cancer of breast	2024-01-01	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000196341	SCV002084803	uncertain significance	Ataxia-telangiectasia syndrome	2021-08-02	no assertion criteria provided	clinical testing