Submissions for variant NM_000051.4(ATM):c.2119T>C (p.Ser707Pro)

gnomAD frequency: 0.00782  dbSNP: rs4986761

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000116422	SCV000150347	benign	not specified	2017-05-18	criteria provided, single submitter	clinical testing
Invitae	RCV000119131	SCV000153845	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000116422	SCV000167069	benign	not specified	2013-09-04	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	RCV000128903	SCV000172764	benign	Hereditary cancer-predisposing syndrome	2014-07-14	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.
Eurofins Ntd Llc (ga)	RCV000116422	SCV000225743	benign	not specified	2015-02-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000128903	SCV000292112	benign	Hereditary cancer-predisposing syndrome	2014-12-04	criteria provided, single submitter	clinical testing
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000116422	SCV000296849	benign	not specified	2015-10-11	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710664	SCV000602556	benign	not provided	2023-11-27	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128903	SCV000679689	likely benign	Hereditary cancer-predisposing syndrome	2018-05-23	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000119131	SCV000743722	likely benign	Ataxia-telangiectasia syndrome	2014-10-09	criteria provided, single submitter	clinical testing
Counsyl	RCV000119131	SCV000789947	likely benign	Ataxia-telangiectasia syndrome	2017-02-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000116422	SCV000805511	benign	not specified	2016-10-10	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710664	SCV000840922	benign	not provided	2017-08-11	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710664	SCV001148408	benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1, BS2
Illumina Laboratory Services, Illumina	RCV000119131	SCV001260415	likely benign	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000116422	SCV002549986	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000116422	SCV002773995	benign	not specified	2021-11-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV003315661	SCV004017070	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315661	SCV005083872	benign	Familial cancer of breast	2024-05-07	criteria provided, single submitter	clinical testing	This variant is considered benign. 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.
ITMI	RCV000116422	SCV000084257	not provided	not specified	2013-09-19	no assertion provided	reference population
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000119131	SCV000732990	benign	Ataxia-telangiectasia syndrome		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000119131	SCV000745808	likely benign	Ataxia-telangiectasia syndrome	2015-11-08	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128903	SCV000787849	likely benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000710664	SCV001553525	likely benign	not provided		no assertion criteria provided	clinical testing	The ATM p.Ser707Pro variant was identified in 542 of 44368 proband chromosomes (frequency: 0.0122) from individuals or families with breast and thyroid cancer and was present in 6 of 1000 control chromosomes (frequency: 0.006) from healthy individuals (Dork 2001, Barbazetto 2008, Dombernowsky 2008, Fletcher 2010, Petereit 2013, Spurdle 2002). The variant was also identified in dbSNP (ID: rs4986761) as other, ClinVar (classified as benign by GeneDx, Ambry genetics, Emory genetics, Color Genomics, Invitae), Cosmic (classified as neutral), MutDB (classified as polymorphism), and LOVD 3.0 databases. The variant was not identified in GeneInsight-COGR and ATM-LOVD databases. The variant was identified in control databases in 2208 of 276136 chromosomes at a frequency of 0.007996 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: European (Non-Finnish) (6 homozygous) in 1508 of 126110 chromosomes (freq: 0.012), Other in 70 of 6438 chromosomes (freq: 0.011). In one study, the p.Ser707Pro variant appeared to be associated with high-risk breast carcinoma, characterized by a positive axillary nodal status and an increased risk of contralateral breast cancer (Dork, 2001). The p.Ser707Pro variant is likely to interfere with secondary and tertiary protein structure, as the exchange of proline for serine introduces a much bulkier side chain and removes a hydroxyl group that possibly participates in hydrogen bonding (Dork, 2001). However, several large population studies have shown that the variant was not associated with an increased breast cancer risk compared with the general population, or overall cancer risk (Barbazetto 2008, Choi 2016, Fletcher 2010, Spurdle 2002). In addition, in their study Thorstenson (2003) found the variant did not segregate with disease. The p.Ser707Pro residue is not conserved in mammals and mammals and the variant amino acid Proline (Pro) is present in several lower organisms, increasing the likelihood that this variant does not have clinical significance. 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. The variant is located with the Armadillo-type fold functional domain(s), the clinical significance of which cannot be determined. 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)	RCV000710664	SCV001799432	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000710664	SCV001906415	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000116422	SCV001918055	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000116422	SCV001956738	benign	not specified		no assertion criteria provided	clinical testing