Submissions for variant NM_000051.4(ATM):c.3331C>G (p.Leu1111Val)

gnomAD frequency: 0.00001  dbSNP: rs587779832

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000587896	SCV000149083	uncertain significance	not provided	2016-05-09	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.3331C>G at the cDNA level, p.Leu1111Val (L1111V) at the protein level, and results in the change of a Leucine to a Valine (CTT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. ATM Leu1111Val 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 Valine share similar properties, this is considered a conservative amino acid substitution. ATM Leu1111Val occurs at a position where amino acids with properties similar to Leucine are tolerated across species and is located in the beta-adaptin interaction domain (Tavtigian 2009). 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 Leu1111Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000206179	SCV000260300	uncertain significance	Ataxia-telangiectasia syndrome	2023-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1111 of the ATM protein (p.Leu1111Val). This variant is present in population databases (rs587779832, gnomAD 0.002%). This missense change has been observed in individual(s) with prostate cancer (PMID: 33436325). ClinVar contains an entry for this variant (Variation ID: 127369). 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.
Ambry Genetics	RCV000568599	SCV000665611	uncertain significance	Hereditary cancer-predisposing syndrome	2022-05-17	criteria provided, single submitter	clinical testing	The p.L1111V variant (also known as c.3331C>G), located in coding exon 22 of the ATM gene, results from a C to G substitution at nucleotide position 3331. The leucine at codon 1111 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in a cohort of 1197 individuals from Greece, Romania, and Turkey referred for multi-gene panel testing for hereditary cancer risk (Tsaousis GN et al. BMC Cancer. 2019 Jun;19:535). This amino acid position is highly 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	RCV000568599	SCV000682119	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1111 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. This variant has been reported in an individual affected with prostate cancer (PMID: 31159747) and in an individual with a personal and/or family history of breast and/or ovarian cancer (PMID: 33436325). This variant has been identified in 2/250664 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587896	SCV000694256	uncertain significance	not provided	2016-08-01	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.3331C>G (p.Leu1111Val) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome for this substitution. This variant is absent in 115192 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Multiple clinical diagnostic laboratories/reputable databases classified this variant as Uncertain. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
GeneKor MSA	RCV000568599	SCV000821847	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262811	SCV001440818	uncertain significance	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing