ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1810C>T (p.Pro604Ser) (rs2227922)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 21
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000120119 SCV000149056 benign not specified 2017-05-26 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 RCV000122824 SCV000166081 benign Ataxia-telangiectasia syndrome 2020-12-04 criteria provided, single submitter clinical testing
Ambry Genetics RCV000115147 SCV000172759 benign Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120119 SCV000225475 likely benign not specified 2015-09-15 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120119 SCV000246612 benign not specified 2018-12-14 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115147 SCV000537384 benign Hereditary cancer-predisposing syndrome 2020-11-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282600 SCV000602566 benign none provided 2020-01-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590282 SCV000694200 benign not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The ATM variant, c.1810C>T (p.Pro604Ser) causes a missense change involving a conserved nucleotide with 2/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 345/111640 (1/323 including 5 homozygotes), which significantly exceeds the estimated maximum expected allele frequency for a pathogenic ATM variant of 1/2000 for Breast Cancer. Therefore, suggesting the variant is a common polymorphism. The variant of interest has been reported in multiple affected individuals via publications with varying phenotypes (BrC, Lynch syndrome, B-CLL, PrC, lymphoma, Hodgkin's disease), including one individual dx with A-T that harbored this variant and another ATM variant, c.6482G>C (p.Arg2161Pro - not yet scored) and was indicated to have absent ATM protein. Two internal LCA samples (adult patients with unknown phenotypes) carried c.1810C>T variant with another pathogenic variants: 1 with a BRIP1 variant, c.440dupA (Tyr147X - classified likely pathogenic) and 1 with an ATM variant, c.1027_1030delGAAA (p.Glu343fsX2 - classified pathogenic). In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available information into consideration for the phenotype of Breast Cancer, the variant of interest is classified as Benign.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000122824 SCV000743721 likely benign Ataxia-telangiectasia syndrome 2015-06-16 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000122824 SCV000745123 uncertain significance Ataxia-telangiectasia syndrome 2016-06-28 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120119 SCV000805505 benign not specified 2016-11-21 criteria provided, single submitter clinical testing
Mendelics RCV000122824 SCV000838494 likely benign Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000122824 SCV001266060 uncertain significance Ataxia-telangiectasia syndrome 2018-01-12 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV001197813 SCV001368593 benign Familial cancer of breast 2018-11-08 criteria provided, single submitter clinical testing This variant was classified as: Benign. The following ACMG criteria were applied in classifying this variant: BS1,BS2.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000590282 SCV001371323 likely benign not provided 2020-04-01 criteria provided, single submitter clinical testing
Molecular Oncology Research Center,Barretos Cancer Hospital RCV001374543 SCV001438622 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-08-01 criteria provided, single submitter research
Nilou-Genome Lab RCV000122824 SCV001737226 benign Ataxia-telangiectasia syndrome 2021-05-18 criteria provided, single submitter clinical testing
ITMI RCV000120119 SCV000084256 not provided not specified 2013-09-19 no assertion provided reference population
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000122824 SCV000745807 likely benign Ataxia-telangiectasia syndrome 2016-07-11 no assertion criteria provided clinical testing
Natera, Inc. RCV000122824 SCV001461084 benign Ataxia-telangiectasia syndrome 2020-04-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356948 SCV001552252 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Pro604Ser variant was identified in 12 of 2910 proband chromosomes (frequency: 0.0041) from individuals or families with breast cancer, ovarian cancer, Ataxia Telangiectasia and several types of lymphomas and was present in 8 of 900 control chromosomes (frequency: 0.009) from healthy individuals (Broeks 2008, Dork 2001, Fang 2003, Gronbaek 2002, Verhagen 2011). The variant was also identified in dbSBP (ID: rs2227922) as “With Likely benign allele”, ClinVar (as likely benign by EGL Diagnostics, Genetic Services Laboratory Chicago, and GeneDx, and as benign by Invitae, Ambry Genetics and Color Genomics), Clinvitae (4x as benign and likely benign), and Cosmic (8x) databases. The variant was not identified in MutDB, LOVD 3.0, ATM-LOVD, databases. The variant was identified in control databases in 887 of 275954 chromosomes at a frequency of 0.003214 in the following populations: Ashkenazi Jewish in 332 (10 homozygous) of 10120 chromosomes (freq. 0.0328), Other in 49 (3 homozygous) of 6424 chromosomes (freq. 0.0076), African in 161 of 23966 chromosomes (freq. 0.0067), Latino in 135 (1 homozygous) of 34286 chromosomes (freq. 0.0039), European (Non-Finnish) in 191 of 126004 chromosomes (freq. 0.0015), South Asian in 16 (1 homozygous) of 30606 chromosomes (freq. 0.0005), and European (Finnish) in 3 of 25730 chromosomes (freq. 0.0001), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). A study of Hodgkin’s lymphoma patients postulated that the p.Pro604Ser variant creates a new glycosylation site which might interfere with ATM function and protein–protein interaction (Offit 2002). The p.Pro604Ser variant was found to co-occur with p.Phe1463Cys in 2 individuals with Non-Hodgkin’s lymphoma (Liberzon 2004). The p.Pro604 residue is conserved in in mammals but not in more distantly related organisms, and the variant amino acid Serine (Ser) is present in the African tree frog, increasing the likelihood that this variant does not have clinical significance. 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 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. 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.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.