Submissions for variant NM_000051.4(ATM):c.4424A>G (p.Tyr1475Cys)

gnomAD frequency: 0.00053  dbSNP: rs34640941

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212017	SCV000149106	likely benign	not specified	2018-01-04	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	RCV000122849	SCV000166107	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115197	SCV000185929	likely benign	Hereditary cancer-predisposing syndrome	2018-10-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000590782	SCV000602575	likely benign	not provided	2017-05-04	criteria provided, single submitter	clinical testing	The p.Tyr1475Cys variant (rs34640941) has not been reported association with ataxia telangiectasia in the medical literature or gene specific variation databases but has been reported to ClinVar (Variation ID: 127392). However, the p.Tyr1475Cys variant has been identified in numerous cancer sequencing cohorts in both case and controls (Fang 2003, Meier 2005, Sipahimalani 2007, Sommer 2003, Tavtigian 2009, Tommiska 2006 and Yurgelun 2015). In a large meta-analysis of breast cancer studies, Tavtigian et al. identified the p.Tyr1475Cys variant in 1/4112 breast cancer cases and 6/2399 controls. Based on these observations the p.Tyr1475Cys variant is likely to be benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212017	SCV000694283	likely benign	not specified	2024-01-05	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4424A>G (p.Tyr1475Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00098 in 1614758 control chromosomes, predominantly at a frequency of 0.0012 within the Non-Finnish European subpopulation in the gnomAD (v4.0.0) database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. In addition, this variant has been reported in 16/7325 European American women, who are older than age 70 and cancer free (in the FLOSSIES database). Multiple publications cite the variant in sequencing studies of affected individuals with varying tumor phenotypes, including breast-, pancreatic- and prostate cancer, lymphoma and Lynch Syndrome, although with limited information (i.e. lack of co-occurrence and cosegregation data). These reports therefore do not provide unequivocal conclusions about association of the variant with Breast Cancer/Ataxia-Telangiectasia. Co-occurrences with other pathogenic variant(s) have been reported (MSH2 c.1861C>T, p.Arg621X, internal testing), providing supporting evidence for a benign role. To our knowledge, no publication reported experimental evidence evaluating an impact on protein function. The following publications have been ascertained in the context of this evaluation (PMID: 17344846, 23555315, 25980754, 16167060, 19781682, 17640065, 20305132, 17333338, 16832357, 16914028, 12697903, 25479140, 12935922, 25862857, 26787654, 26898890, 26976419, 23369113, 27978560, 28652578, 27782108). ClinVar contains an entry for this variant (Variation ID: 127392). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl	RCV000122849	SCV000799741	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-03	criteria provided, single submitter	clinical testing
Mendelics	RCV000122849	SCV000838542	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115197	SCV000910566	likely benign	Hereditary cancer-predisposing syndrome	2014-12-29	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590782	SCV001148422	likely benign	not provided	2024-07-01	criteria provided, single submitter	clinical testing	ATM: BP4
Illumina Laboratory Services, Illumina	RCV000122849	SCV001263904	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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Division of Medical Genetics, University of Washington	RCV001250427	SCV001424785	uncertain significance	Familial cancer of breast	2019-01-03	criteria provided, single submitter	clinical testing	This variant has been reported in individuals with breast cancer (Tung 2016, Tommiska 2006), as well as control populations (Hirsch 2008, Sommer 2003). The c.4424A>G variant has an overall allele frequency of 0.0006 in the Genome Aggregation Database (gnomad.broadinstitute.org). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001281009	SCV001468412	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-03-30	criteria provided, single submitter	clinical testing	ATM NM_000051.3 exon 29 p.Tyr1475Cys (c.4424A>G): This variant has been reported in the literature as germline in at least 6 individuals with various types of cancer (breast, colon, lymphoma) (Sipahimalani 2007 PMID:17640065, Tavtigian 2009 PMID:19781682, Yurgelun 2015 PMID:19781682, Tung 2016 PMID:26976419, Pearlman 2017 PMID:27978560). However, this variant has also been identified in controls (Tavtigian 2009 PMID:19781682) and is present in 0.1% (26/25072) of Finnish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108160516-A-G?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:127392). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590782	SCV001469353	likely benign	not provided	2019-11-27	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000122849	SCV001530024	uncertain significance	Ataxia-telangiectasia syndrome	2018-11-15	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000122849	SCV001716381	uncertain significance	Ataxia-telangiectasia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000212017	SCV001879473	likely benign	not specified	2021-03-19	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798316	SCV002042213	uncertain significance	Breast and/or ovarian cancer	2021-07-30	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212017	SCV002070923	uncertain significance	not specified	2020-12-30	criteria provided, single submitter	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.4424A>G, in exon 29 that results in an amino acid change, p.Tyr1475Cys. This sequence change has been described in the gnomAD database with a frequency of 0.1% in the Finnish sub-population (dbSNP rs34640941). The p.Tyr1475Cys change has been identified in a female with breast cancer (PMID: 26976419) and in an individual with colon cancer (PMID: 27978560). The p.Tyr1475Cys change affects a poorly conserved amino acid residue located in a domain of the ATM protein that is not known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Tyr1475Cys substitution. Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Tyr1475Cys change remains unknown at this time.
Sema4, Sema4	RCV000115197	SCV002534745	likely benign	Hereditary cancer-predisposing syndrome	2021-06-16	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212017	SCV004027227	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001250427	SCV005083995	likely benign	Familial cancer of breast	2024-05-17	criteria provided, single submitter	clinical testing	This variant is considered likely 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].
True Health Diagnostics	RCV000115197	SCV000805217	likely benign	Hereditary cancer-predisposing syndrome	2018-04-26	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549553	SCV000805565	likely benign	ATM-related disorder	2021-02-11	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc.	RCV000122849	SCV001462325	likely benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355381	SCV001550254	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Tyr1475Cys variant was identified in 4 of 1802 proband chromosomes (frequency: 0.002) from African-American, American, Finnish, Dutch and German individuals or families with breast cancer (unselected for history) or childhood acute lymphocytic leukemia; and was present in 1 of 856 control chromosomes (frequency: 0.001) from healthy individuals (Hirsch 2008, Tung 2016, Tommiska 2006, Meier 2005). The variant was also identified in the following databases: dbSNP (ID: rs34640941) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity, sumbitters: uncertain significance by GeneDx; likely benign by Invitae and Ambry Genetics), Clinvitae (3x), Cosmic (1x in a diffuse large b cell lymphoma) and was not identified in the COGR, MutDB, LOVD 3.0 or ATM-LOVD databases. The variant was identified in control databases in 152 of 276060 chromosomes at a frequency of 0.0006 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). It was identified in the following populations: African in 5 of 23840 chromosomes (frequency: 0002), Other in 4 of 6426 chromosomes (frequency: 0006), Latino in 10 of 34336 chromosomes (frequency: 0003), European Non-Finnish in 109 of 126152 chromosomes (frequency: 0.0009), and European Finnish in 24 of 25740 chromosomes (frequency: 005). The p.Tyr1475 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. This variant is classified as a variant of uncertain significance.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115197	SCV002506592	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-20	no assertion criteria provided	clinical testing