Submissions for variant NM_000051.4(ATM):c.6108T>C (p.Tyr2036=)

gnomAD frequency: 0.00017  dbSNP: rs3092826

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165201	SCV000215913	likely benign	Hereditary cancer-predisposing syndrome	2014-07-30	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001085669	SCV000261837	benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165201	SCV000682308	likely benign	Hereditary cancer-predisposing syndrome	2015-10-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586950	SCV000694318	benign	not specified	2019-05-17	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6108T>C alters a non-conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.00027 in 251388 control chromosomes, predominantly within the East Asian subpopulation at a frequency of 0.0034 in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-fold of 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 East Asian origin. Moreover, the variant was also reported in Japanese healthy controls with an even higher frequency (i.e. 0.005), further supporting that the variant is a benign polymorphism found primarily in populations of East Asian origin (HGVD). In a recent case-control association study the variant was found at a similar frequency in female breast cancer patients (44/7051) and controls (67/11241) of Japanese ancestry, and the variant was indicated to be not associated with an increased cancer risk (OR: 1.0) (Momozawa 2018). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as benign (1x) / likely benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Illumina Laboratory Services, Illumina	RCV001085669	SCV001263994	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-28	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.
GeneDx	RCV001528538	SCV001847006	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165201	SCV002537077	benign	Hereditary cancer-predisposing syndrome	2020-08-04	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001528538	SCV005050659	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	ATM: BP4, BP7
Myriad Genetics, Inc.	RCV004589768	SCV005084016	benign	Familial cancer of breast	2024-06-03	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356445	SCV001551615	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Tyr2036= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, LOVD 3.0, databases. The variant was identified in dbSNP (ID: rs3092826) as “With Likely benign allele ", ClinVar (classified as benign by Invitae; as likely benign by Ambry Genetics, Color Genomics, Integrated Genetics/Laboratory Corporation of America), and in Cosmic (1x in Large intestine) databases. The variant was identified in control databases in 73 of 277148 chromosomes at a frequency of 0.00026 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: African in 1 of 24032 chromosomes (freq: 0.00004), Other in 1 of 6464 chromosomes (freq: 0.0002), Latino in 1 of 34416 chromosomes (freq: 0.00003), East Asian in 69 of 18844 chromosomes (freq: 0.004), and South Asian in 1 of 30780 chromosomes (freq: 0.00003), while the variant was not observed in the European, Ashkenazi Jewish, and Finnish populations. The p.Tyr2036= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528538	SCV001740416	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528538	SCV001954077	likely benign	not provided		no assertion criteria provided	clinical testing