Submissions for variant NM_000051.4(ATM):c.2021A>G (p.His674Arg)

gnomAD frequency: 0.00007  dbSNP: rs201762714

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129577	SCV000184359	likely benign	Hereditary cancer-predisposing syndrome	2019-07-17	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	RCV000168255	SCV000218926	likely benign	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000236547	SCV000292868	uncertain significance	not provided	2023-06-13	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 19781682, 26787654, 26689913, 28779002, 27043212, 28873162, 28652578, 31159747, 33471991, 31206626, 32283892, 35264596)
Fulgent Genetics, Fulgent Genetics	RCV000515195	SCV000611347	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000129577	SCV000821833	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV000168255	SCV000838496	benign	Ataxia-telangiectasia syndrome	2023-08-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129577	SCV000902744	likely benign	Hereditary cancer-predisposing syndrome	2016-03-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780908	SCV000918548	likely benign	not specified	2023-03-20	criteria provided, single submitter	clinical testing	Variant summary: ATM c.2021A>G (p.His674Arg) results in a non-conservative amino acid change in 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 0.00016 in 255894 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. This frequency (0.00085) is somewhat lower than the estimated maximum expected for a pathogenic variant in ATM causing Breast Cancer (0.001), allowing no clear conclusions about variant significance. However, the variant was also reported in 3/7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database), supporting a benign role for the variant. c.2021A>G has been reported in the literature in individuals with a personal and/or family history of breast/ovarian cancer, and other tumor phenotypes (e.g. Young_2015, Tsaousis_2019, Weitzel_2019, Erdm_2020, Guindalini_2022), as well as in controls (e.g. Tavtigian_2009). In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 10/60466 cases, but was also found in 10/53461 controls (Dorling_2021, reported through LOVD). A co-occurrence with another pathogenic variant has been reported internally (CHEK2 c.1368dupA, p.Glu457fsX33), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. 1Eleven other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, mostly without evidence for independent evaluation, and classified the variant VUS (n=8), or likely benign (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen	RCV000236547	SCV001148407	uncertain significance	not provided	2019-05-01	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000236547	SCV002010842	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000129577	SCV002534022	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-30	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780908	SCV002760526	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000168255	SCV004234543	uncertain significance	Ataxia-telangiectasia syndrome	2023-07-25	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492590	SCV004240369	uncertain significance	Breast and/or ovarian cancer	2023-04-26	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589624	SCV005083563	likely benign	Familial cancer of breast	2024-05-06	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].
Mayo Clinic Health System - Franciscan Health care, Mayo Clinic Health System	RCV000181010	SCV000233284	uncertain significance	Bilateral breast carcinoma	2014-09-25	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356825	SCV001552094	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.His674Arg variant was identified in the ATM mutation-screening data from the literature study in 1 of 4798 (freq. 0.0002) control chromosomes from healthy individuals and was not identified in 8224 proband chromosomes from individuals or families with breast cancer (Tavtigian 2009). The variant was also identified in dbSNP (ID: rs201762714) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by GeneDx, Invitae, Ambry Genetics and four other submitters). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 45 of 277138 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Latino in 5 of 34418 chromosomes (freq: 0.0002), European in 14 of 126640 chromosomes (freq: 0.0001), and South Asian in 26 of 30782 chromosomes (freq: 0.0009), while the variant was not observed in the African, Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.His674 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) 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. This variant is classified as a variant of uncertain significance.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000236547	SCV001906107	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000236547	SCV001953372	likely benign	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004551243	SCV004720043	likely benign	ATM-related disorder	2024-01-19	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).