Submissions for variant NM_000051.4(ATM):c.2289T>A (p.Phe763Leu)

gnomAD frequency: 0.00096  dbSNP: rs34231402

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211979	SCV000149061	likely benign	not specified	2017-11-20	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.
Invitae	RCV000122834	SCV000166092	benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115152	SCV000172935	likely benign	Hereditary cancer-predisposing syndrome	2018-08-24	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.
Fulgent Genetics, Fulgent Genetics	RCV000515303	SCV000611351	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211979	SCV000694216	benign	not specified	2021-10-18	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2289T>A (p.Phe763Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00071 in 252946 control chromosomes, predominantly at a frequency of 0.002 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. The variant has been identified in numerous patients with HBOC or other types of cancer and control cohorts reported in the literature, without evidence for causality. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with a pathogenic variant has been reported (SMAD4 c.1194G>A, p.W398Ter, Martin-Morales_2018), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Benign n =4, likely benign n=5, VUS n=3). Based on the evidence outlined above, the variant was classified as benign.
PreventionGenetics, part of Exact Sciences	RCV000588896	SCV000805515	likely benign	not provided	2017-11-29	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115152	SCV000821837	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000122834	SCV000838502	likely benign	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115152	SCV000902588	benign	Hereditary cancer-predisposing syndrome	2015-11-10	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000122834	SCV001262547	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000211979	SCV001469347	benign	not specified	2021-08-12	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000211979	SCV001474788	benign	not specified	2020-07-02	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588896	SCV001747027	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798311	SCV002041968	likely benign	Breast and/or ovarian cancer	2022-12-23	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115152	SCV002529843	likely benign	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000588896	SCV002541170	uncertain significance	not provided	2021-04-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211979	SCV004027174	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589556	SCV005083883	likely benign	Familial cancer of breast	2024-05-08	criteria provided, single submitter	clinical testing	This variant is considered likely 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].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355251	SCV001550080	likely benign	Familial ovarian cancer		no assertion criteria provided	clinical testing	The ATM p.Phe763Leu variant was identified in 10 of 8114 proband chromosomes (frequency: 0.0012) from individuals or families with breast cancer, Hodgkin’s Disease and individuals testing for Lynch Syndrome; the variant was present in 7 of 5394 control chromosomes (frequency: 0.012) from healthy individuals (Sommer_2002_11996792, Offit_2002_12473594, Hirsch_2008_17333338, Paglia_2010_19404735, Tavtigian-2009_19781682, Yurgelun_2015_22529920). The variant was also identified in dbSNP (ID: rs34231402) as “With Uncertain significance allele”, ClinVar (2x as uncertain significance by GeneDx and Flugent Genetics, 1x as likely benign by Ambry Genetics, 1x as benign by Invitae), Clinvitae (3x as likely benign and uncertain significance) databases. The variant was not identified in Cosmic, MutDB and LOVD 3.0, databases. The variant was identified in control databases in 186 of 277044 chromosomes (1 homozygous) at a frequency of 0.0007 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 42 of 24034 chromosomes (freq: 0.0012), Other in 14 of 6462 chromosomes (freq: 0.002), Latino in 63 of 34418 chromosomes (freq: 0.002), European Non-Finnish in 54 of 126666 chromosomes (freq: 0.0004), Ashkenazi Jewish in 13 of 10152 chromosomes (freq: 0.0013), while the variant was not observed in the East Asian, European Finnish, and South Asian populations. The p.Phe763Leu residue is conserved in in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; 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.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000588896	SCV001806797	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000588896	SCV001906357	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588896	SCV001952451	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000588896	SCV002036006	likely benign	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115152	SCV002050281	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-27	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122834	SCV002079650	likely benign	Ataxia-telangiectasia syndrome	2020-04-03	no assertion criteria provided	clinical testing