Submissions for variant NM_000051.4(ATM):c.4362A>C (p.Lys1454Asn)

gnomAD frequency: 0.00026  dbSNP: rs148993589

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212012	SCV000149100	uncertain significance	not provided	2022-06-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with breast, endometrial, or colon cancer (Maillet 2002, Broeks 2008, Tavtigian 2009, Lu 2015, Tung 2015, Ring 2016, Decker 2017, Pearlman 2017, Hampel 2018, Hauke 2018); Observed in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008); This variant is associated with the following publications: (PMID: 19781682, 12362033, 17393301, 22529920, 26689913, 12697903, 11505391, 27978560, 27443514, 25925381, 28779002, 25186627, 29522266, 29596542, 30197789, 10425038, 27150160, 25759019, 18502988, 33471991)
Ambry Genetics	RCV000115191	SCV000186552	benign	Hereditary cancer-predisposing syndrome	2015-06-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080906	SCV000254104	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115191	SCV000682199	likely benign	Hereditary cancer-predisposing syndrome	2020-08-12	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212012	SCV000883421	uncertain significance	not provided	2017-07-03	criteria provided, single submitter	clinical testing	The p.Lys1454Asn variant has been reported in individuals with breast cancer (Broeks 2008 Teraoka 2001, Tavtigian 2009), endometrial cancer (Ring 2016), and idiopathic perifoveal telangiectasia (Barbazetto 2008) but has not been reported in association with ataxia telangiectasia. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03 percent (identified on 84 out of 276,958 chromosomes) and has been reported to ClinVar (Variation ID: 127386). The lysine at position 1454 is moderately conserved (Alamut v.2.9.0) and computational analyses of the effects of the p.Lys1454Asn variant on protein structure and function predict a neutral effect (SIFT: tolerated, Align GVGC: C0 (benign), PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Lys1454Asn variant with certainty.
Athena Diagnostics	RCV000212012	SCV001143108	uncertain significance	not provided	2023-08-07	criteria provided, single submitter	clinical testing	Available data are insufficient to determine the clinical significance of the variant at this time. The frequency of this variant in the general population is higher than would generally be expected for pathogenic variants in this gene (http://gnomad.broadinstitute.org). Computational tools disagree on the variant's effect on normal protein function.
CeGaT Center for Human Genetics Tuebingen	RCV000212012	SCV001148421	uncertain significance	not provided	2023-09-01	criteria provided, single submitter	clinical testing	ATM: PM2
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193007	SCV001361526	likely benign	not specified	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4362A>C (p.Lys1454Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 259596 control chromosomes, predominantly at a frequency of 0.0006 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0003 vs 0.004), allowing no conclusion about variant significance. c.4362A>C has been reported in the literature in individuals undergoing multigene panel testing for a variety of hereditary cancers without strong evidence for causality (e.g. Broeks_2008, Tavtigian_2009, Tung_2015, Dalmasso_2021, Karlsson_2021). These reports do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 17393301, 18502988, 19781682, 22529920, 20305132, 17623063, 25186627, 10425038, 28652578, 30447919, 30584090, 31173964, 33436325, 34262154). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=5) and VUS (n=8). Some submitters cite overlapping evidence utilized in the context of this evaluation. Based on the absence of any concrete evidence supporting an actionable outcome in over 5 years of review performed at our laboratory and in the literature as evidence outlined above, the variant was re-classified as likely benign.
Division of Medical Genetics, University of Washington	RCV001257478	SCV001434284	uncertain significance	Familial cancer of breast	2019-11-25	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in individuals with breast cancer and in an individual with endometrial cancer (Teraoka 2001, Broeks 2008, Tavtigian 2009, Lu 2015, Ring 2016), as well as in an individual with idiopathic perifoveal telangiectasia (Barbazetto 2008). This variant has an overall allele frequency of 0.0003 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212012	SCV001469352	uncertain significance	not provided	2023-08-07	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00058 (75/129022 chromosomes in European (Non-Finnish) subpop subpopulation, http://gnomad.broadinstitute.org), is higher than would generally be expected for pathogenic variants in this gene. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 28779002 (2017), 19781682 (2009), 17393301 (2008), 11505391 (2001)), endometrial cancer (PMID: 27443514 (2016)), colorectal cancer (PMID: 27978560 (2016)), pancreatic cancer (PMID: 33436325 (2021)), melanoma (PMID: 34262154 (2021)), or chronic lymphocytic leukemia (PMID: 28652578 (2017)), as well as an individual with perifoveal telangiectasia (PMID: 18502988 (2008)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000212012	SCV002010814	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115191	SCV002534667	likely benign	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001193007	SCV002760567	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV001080906	SCV004048374	uncertain significance	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	The amino acid Lys at position 1454 is changed to a Asn changing protein sequence and it might alter its composition and physico-chemical properties. The missense variant c.4362A>C (p.Lys1454Asn) in ATM gene has been submitted to ClinVar as a Variant of Uncertain Significance, but no details are available for independent assessment. It has not been reported in affected individuals. The p.Lys1454Asn variant is reported with the allele frequency of 0.02937% in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. In silico tools predict the variant to be tolerated. The residue is conserved across species. The amino acid change p.Lys1454Asn in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Myriad Genetics, Inc.	RCV001257478	SCV005083982	likely benign	Familial cancer of breast	2024-05-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Mayo Clinic Laboratories, Mayo Clinic	RCV000212012	SCV005412462	uncertain significance	not provided	2023-09-05	criteria provided, single submitter	clinical testing	BP4
PreventionGenetics, part of Exact Sciences	RCV004739391	SCV000805560	uncertain significance	ATM-related disorder	2024-06-18	no assertion criteria provided	clinical testing	The ATM c.4362A>C variant is predicted to result in the amino acid substitution p.Lys1454Asn. This variant has been observed among multiple patients with sporadic and familial breast cancer, some of whom had additional variants in the BRCA1 or BRCA2 genes; however, this variant was also detected in controls in at least one study (Teraoka et al. 2001. PubMed ID: 11505391; Maillet et al. 2002. PubMed ID: 12362033; Broeks et al. 2008. PubMed ID: 17393301; Tavtigian et al. 2009, Table S2, PubMed ID: 19781682; Table S12, Lu et al. 2015. PubMed ID: 26689913). It has also been reported in individuals with early-onset colorectal cancer (Pearlman et al. 2017. eTable 2, PubMed ID: 27978560), endometrial cancer (Ring et al. 2016, Table S2, PubMed ID: 27443514) and bilateral idiopathic perifoveal telangiectasia (Barbazetto et al. 2008. PubMed ID: 18502988). In addition, Fang et al. has mentioned it as a somatic variant in mantle cell lymphoma (Fang et al. 2003. PubMed ID: 12697903). This variant has been reported at a frequency of ~0.06% in individuals of non-Finnish European origin in the gnomAD database. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127386/). While this variant may be benign, at this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000212012	SCV001554023	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Lys1454Asn variant was identified in 6 of 10774 proband chromosomes (frequency: 0.00056) from individuals or families with breast and colon cancer (Barbazetto_2008, Broeks_2008, Maillet_2002, Pearlman_2016, Tavtigian_2009, Teraoka_2001). The variant was also identified in dbSNP (ID: rs148993589) as “With Uncertain significance allele”, ClinVar (as benign by Ambry Genetics and as uncertain significance by GeneDx, Invitae, and Color Genomics), Clinvitae (as in ClinVar), and in Cosmic. The variant was not identified in the COGR, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 84 of 276958 chromosomes at a frequency of 0.000303 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24022 chromosomes (freq: 0.000042), Other in 1 of 6452 chromosomes (freq: 0.000155), European (Non-Finnish) in 76 of 126554 chromosomes (freq: 0.000601), Ashkenazi Jewish in 3 of 10138 chromosomes (freq: 0.000296), and European (Finnish) in 3 of 25770 chromosomes (freq: 0.000116); it was not observed in the Latino, East Asian, and South Asian populations. The p.Lys1454Asn residue is not conserved in mammals and four out of five 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 was identified in a laboratory in one individual with a co-occurring pathogenic BRCA2 variant p.Gln2943ArgfsX33 in a family with HBOC, increasing the likelihood that the p.Lys1454Asn variant does not have clinical significance. 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.
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000212012	SCV001964870	likely benign	not provided		no assertion criteria provided	clinical testing