rs139552233
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000051.4(ATM):c.2932T>C(p.Ser978Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000806 in 1,613,970 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S978Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_000051.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ATM | NM_000051.4 | c.2932T>C | p.Ser978Pro | missense_variant | 20/63 | ENST00000675843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ATM | ENST00000675843.1 | c.2932T>C | p.Ser978Pro | missense_variant | 20/63 | NM_000051.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000440 AC: 67AN: 152138Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000951 AC: 239AN: 251278Hom.: 2 AF XY: 0.00124 AC XY: 169AN XY: 135814
GnomAD4 exome AF: 0.000844 AC: 1234AN: 1461714Hom.: 7 Cov.: 36 AF XY: 0.000945 AC XY: 687AN XY: 727166
GnomAD4 genome ? AF: 0.000440 AC: 67AN: 152256Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36AN XY: 74454
ClinVar
Submissions by phenotype
not provided Uncertain:5Benign:5
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Mar 20, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | ATM: BS1 - |
Benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 18, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 29, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
Ataxia-telangiectasia syndrome Uncertain:2Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Aug 17, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Apr 09, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 09, 2020 | - - |
not specified Uncertain:1Benign:4
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 26, 2021 | 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. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 17, 2017 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 24, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 22, 2016 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 05, 2015 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 19, 2017 | 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. - |
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jun 01, 2021 | - - |
Breast and/or ovarian cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 05, 2023 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | 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. - |
Familial cancer of breast Benign:1
Benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | May 10, 2024 | 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]. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at