Submissions for variant NM_000051.4(ATM):c.998C>T (p.Ser333Phe)

gnomAD frequency: 0.00137  dbSNP: rs28904919

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120169	SCV000149186	likely benign	not specified	2017-12-11	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV000988648	SCV000153977	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115277	SCV000172886	likely benign	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000586032	SCV000602564	likely benign	not provided	2022-03-28	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115277	SCV000682544	likely benign	Hereditary cancer-predisposing syndrome	2015-02-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586032	SCV000694395	likely benign	not provided	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: ATM c.998C>T affects a conserved nucleotide, resulting in an amino acid change from Ser to Phe. 2/3 in-silico tools predict this variant to be damaging (SNPs&GO and MutationTaster not captured due to low reliability index).This variant was found in patients with MCL, idiopathic juxtafoveolar retinal telangiectasia, breast cancer, CLL, and CRC in germline and in tumor samples. However, co-segregation data were not available in these studies to establish causality of this variant in many studies. In one breast cancer family published in the literature, only the index patient had the variant while 3 affected sisters did not (Tommiska_2006), suggesting that this variant was not causative. The variant of interest was also found in 165/125148 control chromosomes at a frequency of 0.0013184. Specifically, in Finnish control population, MAF of this variant is 0.004548, which is greater than the estimated maximal expected frequency of a pathogenic ATM allele for AT (0.003953) or breast cancer (0.0005001), suggesting this variant is benign. In addition, multiple clinical laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant was classified as Likely Benign until additional information is available.
PreventionGenetics, part of Exact Sciences	RCV000586032	SCV000805637	likely benign	not provided	2017-03-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000988648	SCV001138443	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000586032	SCV001148402	likely benign	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ATM: BP1, BP4, BS2
Illumina Laboratory Services, Illumina	RCV000988648	SCV001263698	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262803	SCV001440807	benign	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115277	SCV001911497	likely benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.998C>T (p.Ser333Phe) missense variant has an allele frequency of 0.16%, (421/268,078 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.35%, (123/35,062 alleles) in the Latino / Admixed American subpopulation (BS1; http://gnomad.broadinstitute.org). This variant has also been observed in homozygosis in 1 individual of the gnomAD v2.1.1 non-neuro dataset and in 1 individual older than 75 year, not affected from ataxia telangiectasia, from the Spanish ATM working group cancer cohort (BS2_Supporting, PMID: 33280026). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. However, the in silico protein effect prediction for this missense variant is inconclusive (no predictive criterion met). Therefore, the variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BS2_Supporting (PMID: 33280026).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798328	SCV002042357	likely benign	Breast and/or ovarian cancer	2023-06-22	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120169	SCV002067112	likely benign	not specified	2022-01-20	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225327	SCV002505050	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115277	SCV002531216	likely benign	Hereditary cancer-predisposing syndrome	2021-03-28	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120169	SCV002760514	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120169	SCV002774007	benign	not specified	2021-12-17	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001262803	SCV005084797	likely benign	Familial cancer of breast	2024-04-24	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].
ITMI	RCV000120169	SCV000084311	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000988648	SCV001461079	likely benign	Ataxia-telangiectasia syndrome	2020-06-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000120169	SCV001553488	benign	not specified		no assertion criteria provided	clinical testing	The ATM p.Ser333Phe variant was identified in 9 (1 homozygous) of 2296 proband chromosomes (frequency: 0.004) from Finnish and American individuals or families with non-BRCA1/2 breast cancer, breast cancer, early onset and familial CRC, and individuals undergoing radiation therapy, and was identified in 37 of8118 chromosomes from healthy (race matched controls) (Petereit 2013, Tommiska 2006, Teraoka 2001, Tanskanen 2015). Segregation studies in 1 family were negative, as the proband’s 3 affected sisters were non-carriers (Tommiska 2006). The variant was also identified in dbSNP (ID: rs28904919) “With Likely benign allele”, ClinVar (classified benign by Invitae, likely benign by GeneDx, Ambry Genetics and ARUP, and classification not provided by ITMI), Clinvitae (3x), Cosmic (2x in a hemangioblastoma and adnexal tumour) and not in MutDB and LOVD 3.0. The variant was identified in control databases in 439 of 276964 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 8 of 24024 chromosomes (freq: 0.0003), Other in 9 of 6462 chromosomes (freq: 0.001), Latino in 125 (1 homozygous) of 34380 chromosomes (freq: 0.004), European Non-Finnish in 209 of 126534 chromosomes (freq: 0.002), European Finnish in 88 of 25784 chromosomes (freq: 0.003), while not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Ser333 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Phe 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 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 this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000586032	SCV001740606	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000586032	SCV001809744	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120169	SCV001905795	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000586032	SCV001919625	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000586032	SCV001928569	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000586032	SCV001957374	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000586032	SCV001973069	likely benign	not provided		no assertion criteria provided	clinical testing