Submissions for variant NM_000051.4(ATM):c.2614C>T (p.Pro872Ser)

gnomAD frequency: 0.01393  dbSNP: rs3218673

Total submissions: 30

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221489	SCV002499289	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.2614C>T (p.Pro872Ser) variant has a GnomAD FAF 4.6% (AFR) exceeding ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous or compound heterozygous state (presumed and/or confirmed) in multiple individuals without Ataxia-Telangiectasia (BP2_Strong, Clinical Diagnostic Laboratories). This variant is predicted tolerated by multiple protein in silico tools (BP4). In summary, this variant meets criteria to be classified as benign. ACMG/AMP criteria applied, as specified by the HBOP Variant Curation Expert Panel.
GeneDx	RCV000120126	SCV000167074	benign	not specified	2013-10-01	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	RCV000128879	SCV000172736	benign	Hereditary cancer-predisposing syndrome	2014-11-25	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)	RCV000120126	SCV000226548	benign	not specified	2015-02-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204457	SCV000262431	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224090	SCV000281433	benign	not provided	2015-12-22	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000204457	SCV000367037	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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000128879	SCV000682065	benign	Hereditary cancer-predisposing syndrome	2014-11-05	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120126	SCV000805522	benign	not specified	2016-10-21	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000224090	SCV000840929	benign	not provided	2018-05-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224090	SCV001477728	benign	not provided	2023-08-24	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225358	SCV002505329	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128879	SCV002532356	benign	Hereditary cancer-predisposing syndrome	2020-03-21	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002498555	SCV002811808	likely benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-03-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149820	SCV003837665	benign	Breast and/or ovarian cancer	2021-07-02	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002221489	SCV004016631	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120126	SCV004027185	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224090	SCV004133251	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1, BS2
Myriad Genetics, Inc.	RCV002221489	SCV005083920	benign	Familial cancer of breast	2024-05-09	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.
Breakthrough Genomics, Breakthrough Genomics	RCV000224090	SCV005231006	benign	not provided		criteria provided, single submitter	not provided
ITMI	RCV000120126	SCV000084264	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000128879	SCV000805214	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000204457	SCV001461093	benign	Ataxia-telangiectasia syndrome	2020-04-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354699	SCV001549380	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Pro872Ser variant was identified in 10 of 1192 proband chromosomes (frequency: 0.008) from individuals or families with breast cancer, multiple myeloma and from breast cancer tumors and was not identified in 200 control chromosomes from healthy individuals (Austen 2008, Rodriguez 2002, Bretsky 2003). The variant was also identified in the following databases: dbSNP (ID: rs3218673) as “With other allele”, in ClinVar (classified as 5x benign and 1x likely benign), Clinvitae (classified as 5x benign and 1x conflicting interpretations of pathogenicity), and Cosmic (1x as neutral). The variant was not identified in the MutDB, LOVD 3.0, or ATM-LOVD databases. The variant was identified in control databases in 1212 of 277156 (32 homozygous) chromosomes at a frequency of 0.004 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%: African in 1102 of 24020 chromosomes (freq: 0.046). The p.Pro872Ser 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 of impact to 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 this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000120126	SCV001740465	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120126	SCV001906188	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000120126	SCV001920784	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000120126	SCV001951509	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000120126	SCV001977987	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224090	SCV002036102	likely benign	not provided		no assertion criteria provided	clinical testing