Submissions for variant NM_000051.4(ATM):c.2932T>C (p.Ser978Pro)

gnomAD frequency: 0.00034  dbSNP: rs139552233

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211991	SCV000149076	benign	not specified	2017-05-17	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000119220	SCV000153964	benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115167	SCV000172932	benign	Hereditary cancer-predisposing syndrome	2017-10-19	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)	RCV000211991	SCV000343835	likely benign	not specified	2016-07-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000584904	SCV000692731	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BS1
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211991	SCV000694240	benign	not specified	2021-07-26	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2932T>C (p.Ser978Pro) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00092 in 266408 control chromosomes, predominantly at a frequency of 0.0049 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.24 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Ataxia-Telangiectasia phenotype (0.004), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. Furthermore, it has also been reported among five individuals who are cancer free at age 70 in the FLOSSIES database. This variant has been reported in multiple affected individuals with classical AT, classical Hodgkins lymphoma, B-NHL, BrC, CRC etc. Among them the one patient with classical AT also carried another ATM variant c.8395-8404del10, and no residual ATM activity was detected via western blot in this patient sample and only about 10% expressed ATM protein detected compared to WT (Carney_2012). However, the possibility of an undetected second variant causing AT in this patient cannot be ruled out. A study evaluating the Rate Ratio of asynchronous contralateral breast cancer associated with ATM gene mutation carrier status found a non-statistically significant risk of contralateral breast cancer for missense variants in the ATM gene (RR 1.2, 95% CI = 0.8 to 1.7) (Bernstein_2010). This low RR and a 95% CI overlapping 1.0 indicate very little confidence in the assertion of association with breast cancer. Subsequently, this variant has been reported in cases and in controls by other studies (example, Dorling_2021). Multiple ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4), likely benign (n=4) and benign (n=5). Based on the evidence outlined above, and the emerging peer consensus, the variant was classified as benign.
Counsyl	RCV000119220	SCV000793508	likely benign	Ataxia-telangiectasia syndrome	2017-08-17	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115167	SCV000821843	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000119220	SCV000838514	likely benign	Ataxia-telangiectasia syndrome	2024-04-09	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000584904	SCV000840931	benign	not provided	2019-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115167	SCV000910564	benign	Hereditary cancer-predisposing syndrome	2015-03-05	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119220	SCV001263808	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000584904	SCV001473207	likely benign	not provided	2020-03-20	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000584904	SCV002010835	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798313	SCV002042027	likely benign	Breast and/or ovarian cancer	2023-06-05	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000211991	SCV002070912	likely benign	not specified	2021-05-24	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115167	SCV002532996	likely benign	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000211991	SCV002760546	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000584904	SCV002774011	benign	not provided	2023-08-29	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000119220	SCV004806644	benign	Ataxia-telangiectasia syndrome	2024-03-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589560	SCV005083933	benign	Familial cancer of breast	2024-05-10	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].
Dr.Nikuei Genetic Center	RCV000119220	SCV005200326	benign	Ataxia-telangiectasia syndrome	2024-07-10	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000119220	SCV001462130	uncertain significance	Ataxia-telangiectasia syndrome	2020-01-09	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356395	SCV001551552	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Ser978Pro variant was identified in 10 of 9598 proband chromosomes (frequency: 0.001) from individuals or families with HBOC, Hereditary Diffuse Gastric Cancer (HDGC), Non-Hodgkin’s lymphoma, Ataxia Telangiectasia (AT), or high risk cancer, and was not identified in 168 control chromosomes from healthy individuals (Yurgelun 2015, Caminsky 2016, Castera 2014, Hansford 2015, Maxwell 2016, Bernstein 2010, Gumy Pause 2006, Carney 2012). The variant co-occurred with an ATM variant (c.8395_8404del) in an AT patient whose residual ATM protein expression level was found to be 10% (Carney 2012). The variant was also identified in dbSNP (ID: rs139552233) “With other allele” and ClinVar (classified as benign by GeneDx, Invitae and Ambry Genetics; as likely benign by EGL Genetic Diagnostics and Counsyl; and as uncertain significance by Praxis fuer Humangentik Tuebingen and Integrated Genetics/Laboratory Corp. of America). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 248 of 277020 chromosomes (2 homozygous) at a frequency of 0.0009, 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: South Asian in 154 (2 homozygous) of 30778 chromosomes (freq: 0.005), Other in 6 of 6456 chromosomes (freq: 0.0009), Latino in 4 of 34408 chromosomes (freq: 0.0001), and European Non-Finnish in 84 of 126608 chromosomes (freq: 0.0007), while it was not observed in the African, Ashkenazi Jewish, East Asian or Finnish populations. The p.Ser978Pro is located in the ß-adaptin binding domain and the p.Ser978 residue is conserved across mammals and other organisms; 5 of 5 computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and only 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000584904	SCV001744664	uncertain significance	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000584904	SCV001800565	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000584904	SCV001921474	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000584904	SCV001952000	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000584904	SCV001975575	uncertain significance	not provided		no assertion criteria provided	clinical testing