Submissions for variant NM_000051.4(ATM):c.2192A>T (p.Tyr731Phe)

gnomAD frequency: 0.00003  dbSNP: rs730881345

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159690	SCV000209696	uncertain significance	not provided	2017-11-14	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.2192A>T at the cDNA level, p.Tyr731Phe (Y731F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Tyr731Phe was not observed in large population cohorts (Lek 2016). Since Tyrosine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. ATM Tyr731Phe is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether ATM Tyr731Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000462835	SCV000546711	uncertain significance	Ataxia-telangiectasia syndrome	2024-10-01	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 731 of the ATM protein (p.Tyr731Phe). 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: 181925). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The phenylalanine 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	RCV000568629	SCV000668067	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.Y731F variant (also known as c.2192A>T), located in coding exon 13 of the ATM gene, results from an A to T substitution at nucleotide position 2192. The tyrosine at codon 731 is replaced by phenylalanine, an amino acid with highly 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.
Baylor Genetics	RCV003467226	SCV004207098	uncertain significance	Familial cancer of breast	2023-09-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355000	SCV001549752	uncertain significance	Endometrial carcinoma		no assertion criteria provided	clinical testing	ATM, EXON14, c.2192A>T, p.Tyr731Phe, Heterozygous, Uncertain SignificancernThe ATM p.Tyr731Phe variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in dbSNP (ID: rs730881345) “With Uncertain significance allele” and ClinVar (classified uncertain significance by Invitae, GeneDx and Ambry Genetics). The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The p.Tyr731 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. Assessment Date: 2019/07/11
Natera, Inc.	RCV000462835	SCV002077143	uncertain significance	Ataxia-telangiectasia syndrome	2021-06-08	no assertion criteria provided	clinical testing