Submissions for variant NM_000051.4(ATM):c.5675-4T>A

dbSNP: rs56075338

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085879	SCV000252966	benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000214255	SCV000274949	likely benign	Hereditary cancer-predisposing syndrome	2020-12-01	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.
GeneDx	RCV000590713	SCV000569622	uncertain significance	not provided	2018-07-06	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5675-4T>A or IVS37-4T>A and consists of a T>A nucleotide substitution at the -4 position of intron 37 of the ATM gene. In silico analyses, which include splice predictors and evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging.? This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. This variant was observed at an allele frequency of 0.15% (47/30,736) in individuals of South Asian ancestry in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether ATM c.5675-4T>A is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590713	SCV000694306	likely benign	not provided	2016-09-30	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.5675-4T>A variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predicting no significant impact on normal splicing and ESE finder predicting the creation of an ESE binding site, however, these predictions have yet to be functionally assessed. The variant of interest has been observed in the large, broad control population, ExAC, with an allele frequency of 35/116558 (1/3330, 1 homozygote), predominantly in the South Asian cohort, 33/15866 (1/480), which exceeds the estimated maximal expected allele frequency for a pathogenic ATM variant of 1/999. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, however, clinical diagnostic laboratories have cited the variant as "likely benign" or "uncertain significance." Therefore, the variant of interest has been classified as Likely Benign.
Color Diagnostics, LLC DBA Color Health	RCV000214255	SCV000910864	likely benign	Hereditary cancer-predisposing syndrome	2015-06-09	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001085879	SCV001262763	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	RCV000214255	SCV002529101	likely benign	Hereditary cancer-predisposing syndrome	2021-09-16	criteria provided, single submitter	curation
Natera, Inc.	RCV001085879	SCV001452118	uncertain significance	Ataxia-telangiectasia syndrome	2020-04-18	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355672	SCV001550623	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM c.5675-4T>A variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs56075338) as "With Uncertain significance allele" and ClinVar (classified as likely benign by Invitae; as uncertain significance by Ambry Genetics, GeneDx, and one other clinical laboratory). The variant was identified in control databases in 48 of 245526 chromosomes (1 homozygous) 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: European in 1 of 111308 chromosomes (freq: 0.000009) and South Asian in 47 of 30736 chromosomes (1 homozygous, freq: 0.0015), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The c.5675-4T>A variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions; positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 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.
PreventionGenetics, part of Exact Sciences	RCV004553073	SCV004747335	likely benign	ATM-related disorder	2019-04-03	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).