Submissions for variant NM_000051.4(ATM):c.1380G>C (p.Thr460=)

dbSNP: rs145333518

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211961	SCV000167063	benign	not specified	2014-02-03	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.
Ambry Genetics	RCV000123720	SCV000213313	likely benign	Hereditary cancer-predisposing syndrome	2014-09-29	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.
Invitae	RCV001079887	SCV000252597	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211961	SCV000593477	likely benign	not specified	2015-09-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000123720	SCV000681974	likely benign	Hereditary cancer-predisposing syndrome	2015-09-22	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589439	SCV000694182	likely benign	not provided	2017-02-16	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.1380G>C (p.Thr460Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide, which 4/5 splice prediction tools predict no significant impact on normal splicing and ESE finder predicts alterations to ESE binding. However, these predictions have yet to be confirmed by functional studies. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 23/121350 (1/5277), predominantly in the African cohort, 21/10404 (1/474), which exceeds the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/999 for Breast Cancer. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. The variant of interest has not been reported, to our knowledge, in affected individuals via publications. However, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as "likely benign."
Eurofins Ntd Llc (ga)	RCV000211961	SCV000861180	likely benign	not specified	2018-05-29	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000589439	SCV001143096	benign	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000123720	SCV001911452	likely benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.1380G>C p.(Thr460=) variant has an allele frequency of 0.00249 (0.24%, 59/ 23608 alleles) in the African population of the gnomAD v2.1.1 non-cancer dataset (BS1; http://gnomad.broadinstitute.org). It is a silent variant not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike – MaxEntScan – NNSplice - GeneSplicer (BP4). The variant is located at a nucleotide that is not highly conserved across species, based on PhyloP (BP7). Therefore, this variant meets criteria to be classified as likely benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BP4 + BP7 (PMID: 33280026).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798411	SCV002042545	likely benign	Breast and/or ovarian cancer	2019-09-09	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000123720	SCV002530331	likely benign	Hereditary cancer-predisposing syndrome	2021-01-28	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315832	SCV004015433	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589439	SCV004219961	benign	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355437	SCV001550321	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Thr460= variant was not identified in the literature. The variant was identified in dbSNP (ID: rs145333518) as "With Likely benign, other allele", ClinVar (classified as benign by GeneDx and Invitae; as likely benign by Ambry Genetics, University of Chicago, Color Genomics, Integrated Genetics and EGL Genetic Diagnostics), and LOVD 3.0 (classified as likely benign by VKGL data sharing initiative).The variant was identified in control databases in 60 of 277138 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 56 of 24028 chromosomes (freq: 0.002), Other in 1 of 6466 chromosomes (freq: 0.0002), Latino in 2 of 34402 chromosomes (freq: 0.00006), European Non-Finnish in 1 of 126658 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Thr460= 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 and the nucleotide is not conserved across mammals. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000589439	SCV002033863	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589439	SCV002038314	likely benign	not provided		no assertion criteria provided	clinical testing