Submissions for variant NM_000051.4(ATM):c.2362A>C (p.Ser788Arg)

gnomAD frequency: 0.00265  dbSNP: rs641252

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120120	SCV000149063	benign	not specified	2015-05-26	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	RCV000115154	SCV000186229	benign	Hereditary cancer-predisposing syndrome	2018-08-30	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000167934	SCV000218582	benign	Ataxia-telangiectasia syndrome	2025-02-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000120120	SCV000226196	benign	not specified	2015-01-07	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120120	SCV000593478	likely benign	not specified	2016-11-23	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115154	SCV000679691	likely benign	Hereditary cancer-predisposing syndrome	2017-07-12	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115154	SCV000682049	benign	Hereditary cancer-predisposing syndrome	2015-10-23	criteria provided, single submitter	clinical testing
Counsyl	RCV000167934	SCV000792122	likely benign	Ataxia-telangiectasia syndrome	2017-06-16	criteria provided, single submitter	clinical testing
Mendelics	RCV000167934	SCV001138472	likely benign	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000167934	SCV001262549	likely benign	Ataxia-telangiectasia syndrome	2017-04-28	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.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115154	SCV001911501	benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.2362A>C p.(Ser788Arg) missense variant has an allele frequency of 0.00944 (0.94%, 223/23,614 alleles) in the African population of the gnomAD v2.1.1 non-cancer dataset. Therefore, this variant meets a stand-alone criterion to be classified as benign (BA1; http://gnomad.broadinstitute.org). Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (PMID: 33280026).
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798312	SCV002041982	likely benign	Breast and/or ovarian cancer	2023-04-25	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115154	SCV002532089	benign	Hereditary cancer-predisposing syndrome	2020-09-09	criteria provided, single submitter	curation
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001729388	SCV003799385	benign	not provided	2023-01-06	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120120	SCV004027175	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589557	SCV005083892	benign	Familial cancer of breast	2024-05-08	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.
CeGaT Center for Human Genetics Tuebingen	RCV001729388	SCV005434332	benign	not provided	2024-10-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1, BS2
ITMI	RCV000120120	SCV000084258	not provided	not specified	2013-09-19	no assertion provided	reference population
True Health Diagnostics	RCV000115154	SCV000787851	likely benign	Hereditary cancer-predisposing syndrome	2017-10-26	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000167934	SCV001462065	benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355240	SCV001550066	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ser788Arg variant was identified in 3 of 3974 proband chromosomes (frequency: 0.00075) from individuals or families with Lynch Syndrome, breast cancer and a general healthy ancestrally diverse cohort in a study of germline variation in cancer-susceptibility genes (Bodian 2014, Yurgelun 2015, Ianuzzi 2002). The variant was also identified in dbSNP (ID: rs641252) as “With other allele” and ClinVar (4x as benign by Invitae, EGL Genetics, Color, GeneDx and 6x as likely benign by University of Chicago Genetic services, Institute for Biomarker, Counsyl, True Health Diagnostics) databases. The variant was not identified in GeneInsight-COGR, Cosmic, MutDB or LOVD 3.0, databases. The variant was identified in control databases in 242 of 276996 chromosomes (2 homozygous) at a frequency of 0.00087 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 230 of 24034 chromosomes (freq: 0.0095), Other in 2 of 6466 chromosomes (freq: 0.0003), Latino in 8 of 34420 chromosomes (freq: 0.0002), European Non-Finnish in 2 of 126668 chromosomes (freq: 0.000016), while the variant was not observed in the Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The p.Ser788Arg 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 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Clinical Genetics, Academic Medical Center	RCV001729388	SCV001979215	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001729388	SCV001980118	likely benign	not provided		no assertion criteria provided	clinical testing