Submissions for variant NM_000051.4(ATM):c.146C>G (p.Ser49Cys)

gnomAD frequency: 0.00712  dbSNP: rs1800054

Total submissions: 35

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221467	SCV002499279	benign	Familial cancer of breast	2022-03-09	reviewed by expert panel	curation	The ATM c.146C>G (p.Ser49Cys) variant has a GnomAD (v2.1.1) filtering allele frequency of 1.208% (NFE) which is above the ATM BA1 threshold of .5% (BA1). This variant has been observed in a homozygous and/or compound heterozygous state (presumed) in multiple individuals without Ataxia-Telangiectasia (Laboratory data) (BP2_Strong). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122818	SCV000166075	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000176968	SCV000167079	benign	not specified	2013-10-03	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	RCV000128940	SCV000172814	benign	Hereditary cancer-predisposing syndrome	2014-06-19	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)	RCV000176968	SCV000228761	benign	not specified	2015-02-27	criteria provided, single submitter	clinical testing
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224620	SCV000280894	likely benign	not provided	2015-09-28	criteria provided, single submitter	clinical testing	Converted during submission to Likely benign.
PreventionGenetics, part of Exact Sciences	RCV000176968	SCV000301652	benign	not specified		criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224620	SCV000493597	benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS1, BS2
Color Diagnostics, LLC DBA Color Health	RCV000128940	SCV000537372	benign	Hereditary cancer-predisposing syndrome	2014-12-08	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000128940	SCV000576455	likely benign	Hereditary cancer-predisposing syndrome	2017-02-14	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000176968	SCV000593473	benign	not specified	2021-05-17	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000224620	SCV000602555	benign	not provided	2023-09-28	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000122818	SCV000743718	likely benign	Ataxia-telangiectasia syndrome	2014-10-09	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000128940	SCV000821790	likely benign	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000176968	SCV000916542	benign	not specified	2018-02-16	criteria provided, single submitter	clinical testing	Variant summary: ATM c.146C>G (p.Ser49Cys) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0072 in 277324 control chromosomes, predominantly within the Non-Finnish European subpopulation at a frequency of 0.013 in the gnomAD database, including 10 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 13 fold above the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001). The allele frequency of this variant in a cohort of individuals who are cancer-free and older than 70 years is 0.025 (185/7325), which is even higher than the allele frequency in the general controls (gnomAD Non-Finnish European, 0.013). These data strongly suggest that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The c.146C>G variant has been reported in the literature in individuals affected with Breast Cancer, though one study reported a lack of cosegregation of the variant with disease in two family members of a proband (Allinen_2002). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. One publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect. A case control study seeking to evaluate whether the variant increases the risk of breast cancer raised the possibility that the variant may be a breast cancer susceptibility allele (Stredrick_2006). However, a much larger cohort from Fletcher_2012 failed to prove the same. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV000122818	SCV001265964	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.
Practice for Gait Abnormalities, David Pomarino, Competency Network Toe Walking c/o Practice Pomarino	RCV001353116	SCV001548277	uncertain significance	Tip-toe gait	2020-10-06	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000122818	SCV001750295	benign	Ataxia-telangiectasia syndrome	2021-07-01	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000176968	SCV001880725	benign	not specified	2021-05-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000176968	SCV002047167	benign	not specified	2021-05-07	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225258	SCV002504913	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000128940	SCV002530420	benign	Hereditary cancer-predisposing syndrome	2020-06-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000176968	SCV002549985	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV002221467	SCV004016475	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002221467	SCV005083844	benign	Familial cancer of breast	2024-04-17	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. 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].
Breakthrough Genomics, Breakthrough Genomics	RCV000224620	SCV005230989	benign	not provided		criteria provided, single submitter	not provided
OMIM	RCV000003189	SCV000023347	risk factor	Breast cancer, susceptibility to	2006-06-01	no assertion criteria provided	literature only
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000122818	SCV000745800	benign	Ataxia-telangiectasia syndrome	2015-11-20	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000128940	SCV000787844	likely benign	Hereditary cancer-predisposing syndrome	2018-02-14	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357240	SCV001552651	benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ser49Cys variant was identified in 84 of 6116 proband chromosomes (frequency: 0.01) from individuals or families with ataxia telangiectasia and breast cancer and was present in 58 of 7048 control chromosomes (frequency: 0.008) from healthy individuals (Castellvi-Bei 1999, Petereit 2013, Schneider 2006, Stedrick 2006). The variant was identified in dbSNP (rs1800054) as “with uncertain significance, other allele”, ClinVar (classified as benign by Color, Ambry Genetics, Invitae and 6 other submitters and likely benign by True Health Diagnostics, University of Chicago and 5 other submitters) and LOVD 3.0 (observed 10x). The variant was identified in control databases in 2005 of 276,924 chromosomes (12 homozygous) at a frequency of 0.007 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 65 of 24,012 chromosomes (freq: 0.003), Other in 30 of 6462 chromosomes (freq: 0.005), Latino in 105 of 34,412 chromosomes (freq: 0.003), European in 1615 of 126,588 chromosomes (freq: 0.01), Ashkenazi Jewish in 6 of 10,148 chromosomes (freq: 0.0006), Finnish in 67 of 25,760 chromosomes (freq: 0.003) and South Asian in 117 of 30,674 chromosomes (freq: 0.004). The variant was not observed in the East Asian population. The variant was expressed in vitro and had reduced but detectable levels of ATM (Becker-Catania 2000). The p.Ser49 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000224620	SCV001800448	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000176968	SCV001905812	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000224620	SCV001924571	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000176968	SCV001952636	benign	not specified		no assertion criteria provided	clinical testing
Natera, Inc.	RCV000122818	SCV002088221	benign	Ataxia-telangiectasia syndrome	2019-11-14	no assertion criteria provided	clinical testing