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

gnomAD frequency: 0.00431  dbSNP: rs2227922

Total submissions: 38

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	2024-02-01	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: 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)	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 Diagnostics, LLC DBA Color Health	RCV000115147	SCV000537384	benign	Hereditary cancer-predisposing syndrome	2020-11-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590282	SCV000602566	benign	not provided	2023-11-29	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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000122824	SCV000745123	uncertain significance	Ataxia-telangiectasia syndrome	2016-06-28	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549541	SCV000805505	benign	ATM-related disorder	2019-05-20	criteria provided, single submitter	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Mendelics	RCV000122824	SCV000838494	likely benign	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, 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 Center for Human Genetics Tuebingen	RCV000590282	SCV001371323	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS2
Molecular Oncology Research Center, Barretos Cancer Hospital	RCV001374543	SCV001438622	uncertain significance	Hereditary breast ovarian cancer syndrome	2020-08-01	criteria provided, single submitter	research
Genome-Nilou Lab	RCV000122824	SCV001737226	benign	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000120119	SCV001879379	benign	not specified	2021-05-07	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115147	SCV001911496	benign	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.1810C>T (p.Pro604Ser) missense variant has an allele frequency of 0.32%, (895/281,544 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.65%, (153/23,556 alleles) in the African subpopulation (BA1; http://gnomad.broadinstitute.org). Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BA1 (+BS2_Supporting) (PMID: 33280026).
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV000120119	SCV001984666	benign	not specified	2020-01-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798309	SCV002043512	benign	Breast and/or ovarian cancer	2019-05-07	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120119	SCV002047276	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	RCV001374543	SCV002505150	benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115147	SCV002533375	benign	Hereditary cancer-predisposing syndrome	2020-06-10	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001197813	SCV004016686	benign	Familial cancer of breast	2023-07-07	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120119	SCV004027164	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001197813	SCV005083857	benign	Familial cancer of breast	2024-05-01	criteria provided, single submitter	clinical testing	This variant is considered benign. 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]. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance.
ITMI	RCV000120119	SCV000084256	not provided	not specified	2013-09-19	no assertion provided	reference population
Genome Diagnostics Laboratory, Amsterdam University Medical Center	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.
GenomeConnect - Invitae Patient Insights Network	RCV000590282	SCV001749879	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 12-22-2014 by GeneDx. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000590282	SCV001905726	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000120119	SCV001922409	benign	not specified		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115147	SCV001950163	benign	Hereditary cancer-predisposing syndrome	2021-09-15	no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590282	SCV001958556	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000590282	SCV001973684	likely benign	not provided		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000590282	SCV002036276	likely benign	not provided		no assertion criteria provided	clinical testing