Submissions for variant NM_000051.4(ATM):c.127C>G (p.Leu43Val)

gnomAD frequency: 0.00001  dbSNP: rs772591447

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000166508	SCV000217307	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	The p.L43V variant (also known as c.127C>G), located in coding exon 2 of the ATM gene, results from a C to G substitution at nucleotide position 127. The leucine at codon 43 is replaced by valine, an amino acid with highly similar properties. 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.
Illumina Laboratory Services, Illumina	RCV000322013	SCV000367019	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000166508	SCV000681963	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 43 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 not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/251228 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000322013	SCV001199503	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-21	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 43 of the ATM protein (p.Leu43Val). This variant is present in population databases (rs772591447, gnomAD 0.01%). 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: 186855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATM protein function with a negative predictive value of 95%. 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.
Baylor Genetics	RCV003462216	SCV004207617	uncertain significance	Familial cancer of breast	2023-10-18	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003462216	SCV005044771	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense c.127C>Gp.Leu43Val variant in ATM gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Leu43Val variant has been reported with allele frequency of 0.01% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance multiple submissions. The amino acid change p.Leu43Val in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Leu at position 43 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356497	SCV001551686	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu43Val variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs772591447) as "With Uncertain significance allele ", and in ClinVar (classified as uncertain significance by Ambry Genetics and Color Genomics) databases. The variant was identified in control databases in 3 of 246084 chromosomes at a frequency of 0.00001 (Genome Aggregation Database Feb 27, 2017). The variant observed in South Asian population in 3 of 30734 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, European, Latino, and Other populations. The p.Leu43 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Natera, Inc.	RCV000322013	SCV002088199	uncertain significance	Ataxia-telangiectasia syndrome	2020-10-19	no assertion criteria provided	clinical testing