Submissions for variant NM_000051.4(ATM):c.5071A>C (p.Ser1691Arg)

gnomAD frequency: 0.00169  dbSNP: rs1800059

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679127	SCV000149113	likely benign	not provided	2021-06-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24728327, 11606401, 26979391, 28652578, 22420423, 22250480, 25742471, 14754616, 19431188, 9463314, 25980754, 26787654, 11505391, 27153395, 28202063, 28196074, 26933808, 28695297, 25133958, 28767289)
Invitae	RCV000119119	SCV000153832	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115204	SCV000187022	benign	Hereditary cancer-predisposing syndrome	2014-06-23	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Eurofins Ntd Llc (ga)	RCV000120143	SCV000345515	benign	not specified	2016-08-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679127	SCV000602571	likely benign	not provided	2023-10-17	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115204	SCV000682248	likely benign	Hereditary cancer-predisposing syndrome	2014-12-04	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000119119	SCV000743730	likely benign	Ataxia-telangiectasia syndrome	2017-06-02	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000119119	SCV000745128	likely benign	Ataxia-telangiectasia syndrome	2016-04-21	criteria provided, single submitter	clinical testing
Counsyl	RCV000119119	SCV000793059	likely benign	Ataxia-telangiectasia syndrome	2017-07-26	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000119119	SCV000803488	benign	Ataxia-telangiectasia syndrome	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Benign, for Ataxia-telangiectasia, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:19431188).
PreventionGenetics, part of Exact Sciences	RCV000679127	SCV000805577	likely benign	not provided	2016-12-12	criteria provided, single submitter	clinical testing
Mendelics	RCV000119119	SCV000838550	benign	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000120143	SCV000916551	benign	not specified	2017-09-19	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.5071A>C (p.Ser1691Arg) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 493/276958 control chromosomes (3 homozygotes) at a frequency of 0.001780, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this variant is likely a benign polymorphism. The variant has been reported in multiple breast cancer cases and cancer families, and in one ataxia-telangiectasia patient. None of the publications provide strong evidence for causality, lacking co-occurrence and co-segregation data, and often not providing the BRCA status of affected individuals. Multiple reputable clinical labs have classified this variant as likely benign/benign, without evidence to independently evaluate. Taken together, based on the prevalence in general population and by applying ACMG rules, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000679127	SCV001148431	likely benign	not provided	2024-02-01	criteria provided, single submitter	clinical testing	ATM: BP1, BP4
Illumina Laboratory Services, Illumina	RCV000119119	SCV001260625	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115204	SCV001911466	benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.5071A>T (p.Ser1691Arg) missense variant has an allele frequency of 0.18%, (476/268,092 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.30%, (354/117,946 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This variant has also been observed in homozygosis in 3 individuals of the gnomAD v2.1.1 non-neuro dataset (BS2_Supporting). Functional studies with the variant protein modelled in an ATM-null lymphoblastoid cell line and proper controls showed that: 1) the level of ATM protein was comparable to that of the positive control; 2) the ability of the modeled protein to phosphorylate Smc1, Nbs1, Chk2, and p53 following exposure of the cells to ionizing radiation and to autophosphorylate serine 1981 was also no different from the positive control; 3)The variant protein formed foci that colocalized with yH2AX following exposure to ionizing radiation (BS3; PMID:19431188). Therefore, this variant meets criteria to be classified as benign. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + BS2_Supporting + BS3 (PMID: 33280026).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798318	SCV002042282	benign	Breast and/or ovarian cancer	2022-07-20	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120143	SCV002070946	likely benign	not specified	2021-09-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115204	SCV002527845	benign	Hereditary cancer-predisposing syndrome	2020-05-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120143	SCV002760582	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120143	SCV002773999	benign	not specified	2021-08-20	criteria provided, single submitter	clinical testing
ITMI	RCV000120143	SCV000084283	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000119119	SCV000732993	likely benign	Ataxia-telangiectasia syndrome		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119119	SCV000745816	likely benign	Ataxia-telangiectasia syndrome	2017-10-26	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000115204	SCV000787870	likely benign	Hereditary cancer-predisposing syndrome	2017-11-14	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000119119	SCV001452116	likely benign	Ataxia-telangiectasia syndrome	2019-12-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354566	SCV001549213	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ser1691Arg variant was identified in 20 of 5886 proband chromosomes (frequency: 0.003) from American, Dutch and Lebanese individuals or families with breast cancer (high risk or familial or nonfamilial) or a history of Lynch syndrome associated cancer and/or polyps or individuals with unspecified cancer undergoing radiotherapy, and was identified in 4 of 3578 control chromosomes from healthy individuals (frequency: 0.001) (Petereit_2013_24416720, Broeks_2008_17393301, Jalkh_2017_28202063, Teraoka_2001_11505391, Bodian_2014_24728327, Yurgelun_2015_25980754 , Stredrick_2006_16652348). Functional studies using an expression construct to model ATM missense variants showed the variant’s level of ATM protein expression and kinase activity was comparable to wildtype (Barone_2009_19431188). The variant was identified in dbSNP (ID: rs1800059) “With other allele”, ClinVar (classified benign by Invitae, Ambry Genetics, EGL Genetic Diagnostics (Eurofins Clinical Diagnostics), likely benign by GeneDx, ARUP and classification not provided by ITMI), Clinvitae (3x), Cosmic (seen 2x in a malignant melanoma, 1x in a haematopoietic neoplasm and 3x in a carcinoma of the large intestine), LOVD 3.0 (1x), and was not identified MutDB. The variant was also identified in control databases in 493 (3 homozygous) of 276958 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 13 of 24030 chromosomes (freq: 0.0005), “Other” in 12 of 6458 chromosomes (freq: 0.002), Latino in 24 of 34416 chromosomes (freq: 0.0007), European Non-Finnish in 372 (2 homozygous) of 126472 chromosomes (freq: 0.003), and European Finnish in 72 (1 homozygous) of 25790 chromosomes (freq: 0.003); it was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Ser1691 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood the variant Arg impacts the protein; however, this information is not predictive enough to rule out 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 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000679127	SCV001800709	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000679127	SCV001905952	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000679127	SCV001955952	likely benign	not provided		no assertion criteria provided	clinical testing