Submissions for variant NM_000051.4(ATM):c.4201T>A (p.Leu1401Ile)

gnomAD frequency: 0.00002  dbSNP: rs587779838

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115188	SCV000149097	uncertain significance	not provided	2017-02-19	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.4201T>A at the cDNA level, p.Leu1401Ile (L1401I) at the protein level, and results in the change of a Leucine to an Isoleucine (TTA>ATA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1401Ile 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 Leucine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1401Ile occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether ATM Leu1401Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000468550	SCV000547021	uncertain significance	Ataxia-telangiectasia syndrome	2022-10-28	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1401 of the ATM protein (p.Leu1401Ile). This variant is present in population databases (rs587779838, gnomAD 0.004%). 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: 127383). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest 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.
Ambry Genetics	RCV000568754	SCV000660496	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-24	criteria provided, single submitter	clinical testing	The p.L1401I variant (also known as c.4201T>A), located in coding exon 27 of the ATM gene, results from a T to A substitution at nucleotide position 4201. The leucine at codon 1401 is replaced by isoleucine, 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.
Color Diagnostics, LLC DBA Color Health	RCV000568754	SCV000906687	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-20	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with isoleucine at codon 1401 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 0/60466 breast cancer cases and 2/53459 controls (OR=0.221, 95%CI 0.01 to 4.902, p-value=0.22; PMID: 33471991). This variant has been identified in 4/250996 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.
Athena Diagnostics	RCV000115188	SCV002771853	uncertain significance	not provided	2022-06-06	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000115188	SCV002034325	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000115188	SCV002037930	likely benign	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000468550	SCV002079269	uncertain significance	Ataxia-telangiectasia syndrome	2021-08-09	no assertion criteria provided	clinical testing