Submissions for variant NM_000051.4(ATM):c.1953A>G (p.Leu651=)

gnomAD frequency: 0.00004  dbSNP: rs730881283

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211970	SCV000209589	benign	not specified	2014-09-23	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.
Ambry Genetics	RCV000159605	SCV000214867	likely benign	Hereditary cancer-predisposing syndrome	2014-08-01	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	RCV001079832	SCV000558341	likely benign	Ataxia-telangiectasia syndrome	2024-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000159605	SCV000682016	likely benign	Hereditary cancer-predisposing syndrome	2016-06-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211970	SCV000694204	likely benign	not specified	2021-01-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000587703	SCV000805510	likely benign	not provided	2017-01-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000159605	SCV002533955	likely benign	Hereditary cancer-predisposing syndrome	2021-07-29	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587703	SCV004220044	likely benign	not provided	2019-08-19	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589657	SCV005084186	benign	Familial cancer of breast	2024-05-02	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	RCV000587703	SCV001551243	likely benign	not provided		no assertion criteria provided	clinical testing	The ATM p.Leu651= variant was identified in 14 of 14208 proband chromosomes (frequency: 0.001) from Japanese individuals or families with breast cancer and was present in 43 of 47462 control chromosomes (frequency: 0.0009) from healthy individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs730881283) “With Uncertain significance allele”, ClinVar (classified as benign by GeneDx; as likely benign by Ambry Genetics, Invitae, Color, and Prevention Genetics; and as uncertain significance by Integrated Genetics/Laboratory Corporation of America), and LOVD 3.0 (1x as benign). The variant was identified in control databases in 22 of 277048 chromosomes at a frequency of 0.00008 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24030 chromosomes (freq: 0.00004), Other in 1 of 6460 chromosomes (freq: 0.0002), Latino in 14 of 34416 chromosomes (freq: 0.0004), European Non-Finnish in 5 of 126592 chromosomes (freq: 0.00004), and South Asian in 1 of 30778 chromosomes (freq: 0.00003), while not observed in the Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Leu651= 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) 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.
Natera, Inc.	RCV001079832	SCV002083960	likely benign	Ataxia-telangiectasia syndrome	2020-03-08	no assertion criteria provided	clinical testing