Submissions for variant NM_000051.4(ATM):c.125A>G (p.His42Arg)

gnomAD frequency: 0.00007  dbSNP: rs201773026

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001719857	SCV000149048	likely benign	not provided	2020-09-08	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115139	SCV000184638	likely benign	Hereditary cancer-predisposing syndrome	2018-05-10	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	RCV000231946	SCV000282868	likely benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000211940	SCV000694175	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing	Variant summary: ATM c.125A>G (p.His42Arg) results in a non-conservative amino acid change located in the Telomere-length maintenance and DNA damage repair domain (IPR021668) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0003 in 298686 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.5-fold the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.125A>G has been reported in the literature in individuals affected with Breast Cancer and/or tested for Hereditary Breast and Ovarian Cancer (e.g. Momozawa_2018, Chen_2019, Shao_2019), but also in healthy controls (e.g. Momozawa_2018). The variant has also been reported in an individual with Biliary Tract cancer (e.g. Terashima_2019). Several large case-control studies evaluating breast cancer/Biliary tract cancer reported the variant Benign or insignificantly distributed between cases and controls (Dorling_2021 through LOVD, Guindalini_2022, Okawa_2023). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31867841, 33471991, 35264596, 23555315, 27093186, 26689913, 30287823, 36243179, 31742824, 31666926). ClinVar contains an entry for this variant (Variation ID: 127335). Based on the evidence outlined above, the variant was classified as likely benign.
Mendelics	RCV000231946	SCV000838466	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115139	SCV000902707	likely benign	Hereditary cancer-predisposing syndrome	2016-07-26	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030450	SCV001193462	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Sema4, Sema4	RCV000115139	SCV002530231	likely benign	Hereditary cancer-predisposing syndrome	2020-10-02	criteria provided, single submitter	curation
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153366	SCV003843375	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003315633	SCV004020274	likely benign	Familial cancer of breast	2023-03-10	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001719857	SCV004219928	likely benign	not provided	2022-08-30	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492452	SCV004240280	likely benign	Breast and/or ovarian cancer	2022-10-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358550	SCV001554317	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.His42Arg variant was not identified in the literature nor was it identified in the following databases: Cosmic, MutDB, and LOVD 3.0. The variant was identified in dbSNP (ID: rs201773026) as “With Uncertain significance allele”, ClinVar (as likely benign by GeneDx and Ambry Genetics and uncertain significance by Invitae), and Clinvitae (6x with conflicting interpretations of pathogenicity). The variant was identified in control databases in 34 of 277040 chromosomes at a frequency of 0.000123 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: European (Non-Finnish) in 1 of 126626 chromosomes (freq: 0.000008), East Asian in 31 of 18868 chromosomes (freq: 0.001643), and South Asian in 2 of 30728 chromosomes (freq: 0.000065); the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, or European (Finnish) populations. The p.His42Arg residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.
PreventionGenetics, part of Exact Sciences	RCV004739385	SCV005355277	likely benign	ATM-related disorder	2024-03-21	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).