Submissions for variant NM_000051.4(ATM):c.6114C>T (p.His2038=)

gnomAD frequency: 0.00004  dbSNP: rs774993357

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167380	SCV000218234	likely benign	Hereditary cancer-predisposing syndrome	2024-02-21	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.
GeneDx	RCV000438751	SCV000515512	benign	not specified	2015-05-18	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000458818	SCV000558457	likely benign	Ataxia-telangiectasia syndrome	2024-01-26	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167380	SCV000687675	likely benign	Hereditary cancer-predisposing syndrome	2017-10-06	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798601	SCV002042721	likely benign	Breast and/or ovarian cancer	2021-04-28	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000438751	SCV002065361	likely benign	not specified	2021-06-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000167380	SCV002537100	likely benign	Hereditary cancer-predisposing syndrome	2020-07-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000438751	SCV004024703	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV004546446	SCV005041549	uncertain significance	not provided	2024-04-01	criteria provided, single submitter	clinical testing	ATM: PM2:Supporting, BP4
Myriad Genetics, Inc.	RCV004589824	SCV005084020	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	RCV001355851	SCV001550856	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.His2038= variant was identified in the literature, although this variant was not reported to be identified in an affected population and was identified in 2 of 22482 control chromosomes (frequency: 0.00009) from healthy individuals (Momozawa 2018). The variant was also identified in dbSNP (ID: rs774993357) as "With Likely benign, Uncertain significance allele", ClinVar (classified as benign by GeneDx; and as likely benign by Invitae, Ambry Genetics and Color), and LOVD 3.0 (1x as benign). The variant was identified in control databases in 9 of 246170 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5480 chromosomes (freq: 0.0002), European in 6 of 111670 chromosomes (freq: 0.00005), and South Asian in 2 of 30780 chromosomes (freq: 0.00007), while the variant was not observed in the African, Latino, Ashkenazi Jewish, East Asian, or Finnish populations. The p.His2038= 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.