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

gnomAD frequency: 0.00018  dbSNP: rs555219189

Total submissions: 9

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)
Invitae	RCV000199179	SCV000254084	likely benign	Ataxia-telangiectasia syndrome	2022-10-31	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: 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.
Natera, Inc.	RCV000199179	SCV001457147	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing