Submissions for variant NM_000051.4(ATM):c.6995T>C (p.Leu2332Pro)

gnomAD frequency: 0.00660  dbSNP: rs4988111

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221490	SCV002499280	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.6995T>C (p.Leu2332Pro) variant has a gnomAD v2.1.1 filtering allele frequency of 2.062% (African/African-American; exomes) which exceeds the ATM BA1 threshold of 0.50% (BA1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 61756, 500031). In silico protein predictors (ALIGN GVGD: Class C25; REVEL: 0.193; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.01/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 9.04, variant = 9.04)) find that this variant is unlikely to affect splicing (BP4). In summary, this variant meets criteria to be classified as benign based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
GeneDx	RCV000120156	SCV000167054	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	RCV000128891	SCV000172751	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.
Invitae	RCV001080466	SCV000262433	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224405	SCV000281631	likely benign	not provided	2016-02-11	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000128891	SCV000682382	benign	Hereditary cancer-predisposing syndrome	2014-11-12	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120156	SCV000703941	benign	not specified	2016-12-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120156	SCV000805611	benign	not specified	2016-10-21	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001080466	SCV001260754	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Athena Diagnostics	RCV000120156	SCV001879541	benign	not specified	2020-10-26	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798379	SCV002042853	benign	Breast and/or ovarian cancer	2019-11-13	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225365	SCV002504763	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224405	SCV002506098	benign	not provided	2023-08-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128891	SCV002536831	benign	Hereditary cancer-predisposing syndrome	2020-03-21	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002483213	SCV002795859	benign	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-04-29	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002221490	SCV004017169	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120156	SCV004024332	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
ITMI	RCV000120156	SCV000084297	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000128891	SCV000805220	likely benign	Hereditary cancer-predisposing syndrome	2018-06-18	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001080466	SCV001452131	benign	Ataxia-telangiectasia syndrome	2020-01-07	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357692	SCV001553236	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Leu2332Pro variant was identified in 6 of 2720 proband chromosomes (frequency: 0.002) from American and Brazilian individuals or families with Lynch syndrome or sporadic breast cancer and was not identified in 200 chromosomes from healthy individuals (Yurgelun_2015_25980754 , Mangone_2015_25625042). The variant was also identified in dbSNP (ID: rs4988111) “With Likely benign, Uncertain significance allele”, ClinVar (classified benign by GeneDx, Ambry Genetics, Invitae; likely benign by Center for Pediatric Genomic Medicine (Children's Mercy Hospital and Clinics); and classification not provided by ITMI), Clinvitae (4x); and was not identified in GeneInsight-COGR, Cosmic, MutDB, and LOVD 3.0. The variant was identified in control databases in 557 (7 homozygous) of 276772 chromosomes at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 515 (7 homozygous) of 24026 chromosomes (freq: 0.02), Other in 4 of 6460 chromosomes (freq: 0.0006), Latino in 27 of 34410 chromosomes (freq: 0.0008), European Non-Finnish in 9 of 126350 chromosomes (freq: 0.00007), Ashkenazi Jewish in 1 of 10138 chromosomes (freq: 0.0001), and South Asian in 1 of 30780 chromosomes (freq: 0.00003) while not observed in the East Asian and European Finnish, populations. The p.Leu2332 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 Pro 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 this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000120156	SCV001739751	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000120156	SCV001906224	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000224405	SCV001955393	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000224405	SCV001965179	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224405	SCV002037012	likely benign	not provided		no assertion criteria provided	clinical testing