Submissions for variant NM_000051.4(ATM):c.749G>A (p.Arg250Gln)

gnomAD frequency: 0.00007  dbSNP: rs56123940

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129173	SCV000183906	likely benign	Hereditary cancer-predisposing syndrome	2018-09-29	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.
GeneDx	RCV001704053	SCV000209681	likely benign	not provided	2020-10-28	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 19404735, 17344846, 22529920, 28779002, 31159747)
Invitae	RCV000204231	SCV000259752	likely benign	Ataxia-telangiectasia syndrome	2024-01-29	criteria provided, single submitter	clinical testing
Counsyl	RCV000204231	SCV000799869	uncertain significance	Ataxia-telangiectasia syndrome	2018-05-15	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000129173	SCV000821872	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492586	SCV000838477	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129173	SCV000910702	likely benign	Hereditary cancer-predisposing syndrome	2015-08-05	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211952	SCV001360414	likely benign	not specified	2021-07-17	criteria provided, single submitter	clinical testing	Variant summary: ATM c.749G>A (p.Arg250Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.8e-05 in 250992 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (4.8e-05 vs 0.004), allowing no conclusion about variant significance. However, the presence of a homozygous occurrence in healthy controls suggests that the variant has a neutral impact. c.749G>A has been reported in the literature in settings of multigene panel testing in individuals affected with various cancer phenotypes without strong evidence for causality (examples-Grennman_2007, LaPaglia_2009, Haiman_2013, Tung_2015, Muller_2015, Tiao_2017, Martin-Moales_2018, Tsaousis_2019, Weitzel_2019, Sandoval_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine 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=4; VUS, n=4). Based on the emerging majority consensus among peers and the evidence outlined above, the variant was re-classified as likely benign.
Division of Medical Genetics, University of Washington	RCV001257469	SCV001434275	uncertain significance	Familial cancer of breast	2019-10-04	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in an individual with breast cancer (Paglia 2010). This variant has an overall allele frequency of 0.00005 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant does not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798434	SCV002042895	uncertain significance	Breast and/or ovarian cancer	2019-05-24	criteria provided, single submitter	clinical testing
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225424	SCV002505028	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129173	SCV002538038	likely benign	Hereditary cancer-predisposing syndrome	2020-12-09	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001704053	SCV002774770	uncertain significance	not provided	2021-07-20	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001704053	SCV002821661	likely benign	not provided	2022-10-01	criteria provided, single submitter	clinical testing	ATM: BP4, BS2
Natera, Inc.	RCV000204231	SCV001454847	likely benign	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV001704053	SCV002075271	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 08-11-2016 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.