Submissions for variant NM_000051.4(ATM):c.186-7C>T

gnomAD frequency: 0.00568  dbSNP: rs55674039

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079259	SCV000166083	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000123747	SCV000167090	benign	not specified	2013-10-11	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.
Color Diagnostics, LLC DBA Color Health	RCV000580817	SCV000682009	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589334	SCV000694202	benign	not provided	2016-03-25	criteria provided, single submitter	clinical testing	Variant summary: The c.186-7C>T variant affects a non-conserved intronic nucleotide. Mutation taster predicts benign outcome for this variant. 5/5 programs in Alamut predict no significant effect on RNA splicing sites. ESE finder predicts that this variant may affect ESE site of SRp40. However, these predictions are not validated by experimental studies yet. This variant is found in 149/83742 control chromosomes, predominantly observed in African subpopulation in ExAC with observed MAF of 0.01887 (139/7368 chr, 1 homozygote), This frequency exceeds the maximal expected frequency of a pathogenic allele (0.0005), suggesting this variant is a benign polymorphism especially for Africans. This variant has been reported in multiple pts with different kinds of cancers (including BrC, T-ALL, AML, LS associated cancer, etc.) without strong evidence for causality. In addition, two clinical laboratories via ClinVar classified this variant as benign, without evidence to independently evaluate. Taken together, this variant was classified as Benign.
PreventionGenetics, part of Exact Sciences	RCV000123747	SCV000805508	benign	not specified	2016-10-03	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001079259	SCV001260300	likely benign	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589334	SCV001473186	benign	not provided	2023-09-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000123747	SCV001474786	benign	not specified	2020-02-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000123747	SCV002070835	benign	not specified	2018-12-19	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225389	SCV002504980	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000580817	SCV002721034	benign	Hereditary cancer-predisposing syndrome	2016-02-06	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.
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315803	SCV004016553	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492530	SCV004240347	benign	Breast and/or ovarian cancer	2023-02-17	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000123747	SCV004243399	benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315803	SCV005083859	benign	Familial cancer of breast	2024-04-18	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. 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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
Natera, Inc.	RCV001079259	SCV001461812	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354839	SCV001549550	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM c.186-7C>T variant was identified in 4 of 2730 proband chromosomes (frequency: 0.00146) from individuals or families with Lynch syndrome (Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSBP (ID: rs55674039) as “With Benign allele,” ClinVar (as benign by GeneDx and Invitae), and Clinvitae (as benign) databases. The variant was not identified in Cosmic, MutDB, LOVD 3.0, ATM-LOVD databases. The variant was identified in control databases in 438 of 270788 chromosomes at a frequency of 0.001618 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the African population at a frequency greater than 1% in 404 (4 homozygous) of 23450 chromosomes (freq: 0.017), and at lower frequencies in the following populations: Other in 3 of 6358 chromosomes (freq. 0.00047), Latino in 24 of 33868 chromosomes (freq. 0.0007), European (Non-Finnish) in 3 of 123042 chromosomes (freq. 0.00002), and South Asian in 4 of 29908 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant. The c.186-7C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000123747	SCV001806915	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000589334	SCV001926578	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000123747	SCV001951405	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000123747	SCV001975018	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000123747	SCV002035548	benign	not specified		no assertion criteria provided	clinical testing