ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.998C>T (p.Ser333Phe) (rs28904919)

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Total submissions: 21
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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 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115277 SCV000172886 likely benign Hereditary cancer-predisposing syndrome 2018-12-17 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001283675 SCV000602564 likely benign none provided 2020-01-16 criteria provided, single submitter clinical testing
Color Health, Inc 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,PreventionGenetics 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 Praxis fuer Humangenetik Tuebingen RCV000586032 SCV001148402 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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).
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
Human Genetics - Radboudumc,Radboudumc RCV000586032 SCV001957374 likely benign not provided no assertion criteria provided clinical testing

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