ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5002C>T (p.Leu1668=)

gnomAD frequency: 0.00002  dbSNP: rs747317946
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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000206796 SCV000260880 likely benign Ataxia-telangiectasia syndrome 2024-01-09 criteria provided, single submitter clinical testing
GeneDx RCV001355666 SCV000512166 likely benign not provided 2019-07-11 criteria provided, single submitter clinical testing
Ambry Genetics RCV000565986 SCV000660475 likely benign Hereditary cancer-predisposing syndrome 2014-11-24 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.
Color Diagnostics, LLC DBA Color Health RCV000565986 SCV000682235 likely benign Hereditary cancer-predisposing syndrome 2016-11-17 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV000206796 SCV001260623 uncertain significance Ataxia-telangiectasia syndrome 2018-01-13 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.
Sema4, Sema4 RCV000565986 SCV002527778 likely benign Hereditary cancer-predisposing syndrome 2021-01-26 criteria provided, single submitter curation
CeGaT Center for Human Genetics Tuebingen RCV001355666 SCV004133258 likely benign not provided 2022-06-01 criteria provided, single submitter clinical testing ATM: BP4, BP7
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001355666 SCV004221138 likely benign not provided 2023-02-23 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV003491959 SCV004239283 likely benign Breast and/or ovarian cancer 2022-10-19 criteria provided, single submitter clinical testing
Myriad Genetics, Inc. RCV004589891 SCV005084086 benign Familial cancer of breast 2024-05-21 criteria provided, single submitter clinical testing This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355666 SCV001550616 likely benign not provided no assertion criteria provided clinical testing The ATM p.Leu1668= 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: rs747317946) as “With Likely benign allele”, in ClinVar (as likely benign by Invitae, GeneDx, Ambry Genetics, and Color Genomics). The variant was identified in control databases in 5 of 245428 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European (Non-Finnish) in 1 of 111058 chromosomes (freq: 0.000009), and Ashkenazi Jewish in 4 of 9832 chromosomes (freq: 0.000407), while the variant was not observed in the African, Other, Latino, East Asian, Finnish, and South Asian populations. The p.Leu1668= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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