ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2932T>C (p.Ser978Pro) (rs139552233)

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Total submissions: 19
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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.
Invitae RCV000119220 SCV000153964 benign Ataxia-telangiectasia syndrome 2020-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115167 SCV000172932 benign Hereditary cancer-predisposing syndrome 2017-10-19 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000211991 SCV000343835 likely benign not specified 2016-07-22 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000584904 SCV000692731 likely benign not provided 2019-11-01 criteria provided, single submitter clinical testing
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 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000584904 SCV000840931 benign not provided 2019-07-18 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115167 SCV000910564 benign Hereditary cancer-predisposing syndrome 2015-03-05 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,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 RCV001286604 SCV001473207 likely benign none provided 2020-03-20 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
Human Genetics - Radboudumc,Radboudumc RCV000584904 SCV001952000 uncertain significance not provided no assertion criteria provided clinical testing

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