Submissions for variant NM_000051.4(ATM):c.1073A>G (p.Asn358Ser)

gnomAD frequency: 0.00079  dbSNP: rs149636614

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221486	SCV002499281	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.1073A>G (p.Asn358Ser) variant has a gnomAD v2.1.1 filtering allele frequency of 0.1523% (African/African-American; exomes) which exceeds the ATM BS1 threshold of 0.05% (BS1). This variant has been observed in a homozygous and compound heterozygous state (presumed) in multiple individuals without biallelic disease (BP2_Strong; GTR Lab IDs: 500031, 61756). In silico protein predictors (ALIGN GVGD: Class C0; REVEL: 0.054; SIFT: tolerated; PolyPhen2: benign) predict that this alteration is not deleterious and in silico splicing predictors (SpliceAI: AL 0.13/DL 0.00/AG 0.00/DG 0.00; MaxEntScan: 0.00% (wild type = 10.82, variant = 10.82)) 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	RCV000587788	SCV000149042	uncertain significance	not provided	2018-10-19	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.1073A>G at the cDNA level, p.Asn358Ser (N358S) at the protein level, and results in the change of an Asparagine to a Serine (AAT>AGT). ATM Asn358Ser was reported in an individual with breast cancer, in an individual with a personal history of a Lynch syndrome-related cancer and/or colon polyps, and in an individual undergoing multigene hereditary cancer panel testing (Yurgelun 2015, Mu 2016, Decker 2017). This variant was observed at an allele frequency of 0.23% (55/23,886) in individuals of African ancestry in large population cohorts (Lek 2016). ATM Asn358Ser is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Asn358Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000115133	SCV000186618	likely benign	Hereditary cancer-predisposing syndrome	2019-03-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000196425	SCV000254054	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211956	SCV000593496	uncertain significance	not specified	2015-09-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211956	SCV000694170	likely benign	not specified	2024-01-08	criteria provided, single submitter	clinical testing	Variant summary: ATM c.1073A>G (p.Asn358Ser) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 1605794 control chromosomes, predominantly at a frequency of 0.0024 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2.4 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. c.1073A>G has been reported in the literature in individuals affected with Breast Cancer (e.g. Decker_2017) and Lynch Syndrome (e.g. Yurgelun_2015). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. The following publications have been ascertained in the context of this evaluation (PMID: 27621404, 28779002, 27720647, 30541756, 28652578, 25980754, 31206626). ClinVar contains an entry for this variant (Variation ID: 127329). Based on the evidence outlined above, the variant was classified as likely benign.
Eurofins Ntd Llc (ga)	RCV000587788	SCV000861181	uncertain significance	not provided	2018-05-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115133	SCV000910676	likely benign	Hereditary cancer-predisposing syndrome	2015-09-23	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000587788	SCV001143095	likely benign	not provided	2019-05-01	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798306	SCV002043511	uncertain significance	Breast and/or ovarian cancer	2019-10-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115133	SCV002529718	likely benign	Hereditary cancer-predisposing syndrome	2021-01-28	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587788	SCV004219918	likely benign	not provided	2022-10-27	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221486	SCV005083832	likely benign	Familial cancer of breast	2024-04-25	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	RCV001355543	SCV001550462	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Asn358Ser variant was identified in 1 of 562 proband chromosomes (frequency: 0.002) from individuals or families with breast cancer and triple-negative breast cancer and was present in 2 of 488 control chromosomes (frequency: 0.004) from healthy individuals (Lovejoy 2018, Rosenstein 2006). The variant was also identified in dbSNP (ID: rs149636614) as "With Uncertain significance allele", ClinVar (classified as likely benign by Ambry Genetics and Integrated Genetics and as uncertain significance by GeneDx, Invitae, University of Chicago and EGL Genetic Diagnostics), LOVD 3.0 (classified as likely benign by VKGL data sharing initiative). The variant was identified in control databases in 60 of 272346 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 55 of 23886 chromosomes (freq: 0.002), Other in 1 of 6350 chromosomes (freq: 0.0002), Latino in 3 of 33660 chromosomes (freq: 0.00009), European Non-Finnish in 1 of 125094 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Asn358 residue is not conserved in mammals and 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) do not 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.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000587788	SCV002034052	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000587788	SCV002037982	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549537	SCV004741836	likely benign	ATM-related disorder	2022-03-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).