Submissions for variant NM_000051.4(ATM):c.3449G>C (p.Arg1150Thr)

gnomAD frequency: 0.00018  dbSNP: rs555219189

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115177	SCV000149086	uncertain significance	not provided	2021-04-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast or ovarian cancer (Singh 2018); This variant is associated with the following publications: (PMID: 29470806, 31919090)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000199179	SCV000254084	likely benign	Ataxia-telangiectasia syndrome	2024-01-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000215488	SCV000278041	likely benign	Hereditary cancer-predisposing syndrome	2021-04-20	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.
Color Diagnostics, LLC DBA Color Health	RCV000215488	SCV000687480	likely benign	Hereditary cancer-predisposing syndrome	2020-10-20	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000115177	SCV001714396	uncertain significance	not provided	2020-03-10	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818259	SCV002068402	uncertain significance	not specified	2018-03-02	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000215488	SCV002536023	likely benign	Hereditary cancer-predisposing syndrome	2021-12-05	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818259	SCV002548067	likely benign	not specified	2022-05-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3449G>C (p.Arg1150Thr) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251216 control chromosomes, predominantly at a frequency of 0.0015 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 1.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM (0.001) causing an ATM-related Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.3449G>C has been reported in the literature as a VUS in settings of multigene panel testing among individuals with a variety of cancers to include breast cancer (example, Singh_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia Telangiectasia/ATM-related cancers. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (Likely benign, n=2; VUS, n=5). Based on the evidence outlined above, the variant was classified as likely benign.
Neuberg Centre For Genomic Medicine, NCGM	RCV003338413	SCV004048513	uncertain significance	Familial cancer of breast		criteria provided, single submitter	clinical testing	The missense variant in c.3449G>C (p.Arg1150Thr) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Arg1150Thr variant is is reported with the allele frequency of 0.01831% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as conflicting - uncertain significance/ likely benign. The amino acid Arg at position 1150 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg1150Thr in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Natera, Inc.	RCV000199179	SCV001457147	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing