Submissions for variant NM_000051.4(ATM):c.5747T>C (p.Met1916Thr)

gnomAD frequency: 0.00001  dbSNP: rs1060501557

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471247	SCV000546715	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1916 of the ATM protein (p.Met1916Thr). 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: 407488). 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.
GeneDx	RCV000482185	SCV000566461	uncertain significance	not provided	2024-03-23	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35585550)
Ambry Genetics	RCV000574580	SCV000667965	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-29	criteria provided, single submitter	clinical testing	The p.M1916T variant (also known as c.5747T>C), located in coding exon 37 of the ATM gene, results from a T to C substitution at nucleotide position 5747. The methionine at codon 1916 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well 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.
Color Diagnostics, LLC DBA Color Health	RCV000574580	SCV000682283	uncertain significance	Hereditary cancer-predisposing syndrome	2022-11-07	criteria provided, single submitter	clinical testing	This missense variant replaces methionine with threonine at codon 1916 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 performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.
MGZ Medical Genetics Center	RCV002289607	SCV002581066	uncertain significance	Familial cancer of breast	2022-07-15	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355236	SCV001550061	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Met1916Thr variant was not identified in the literature nor was it identified in the dbSNP, GeneInsight-COGR, Cosmic, MutDB, LOVD 3.0, ATM-LOVD, databases. The variant was identified in ClinVar (classified as uncertain significance by Invitae, GeneDx) database. The variant was not identified in the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Met1916 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.