Submissions for variant NM_000051.4(ATM):c.7390T>C (p.Cys2464Arg)

gnomAD frequency: 0.00038  dbSNP: rs55801750

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589438	SCV000149158	likely benign	not provided	2021-09-22	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30093976, 30303537, 30197789, 17623063, 20305132, 22250480, 21933854, 23555315, 25479140, 28135145, 28779002, 25587027, 15279808, 22420423, 12810666, 27978560, 27878467, 26787654, 17344846, 11805335, 11606401, 11839094, 16652348, 12673804, 23091097, 22529920, 19781682)
Invitae	RCV000119204	SCV000153946	benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115249	SCV000186389	benign	Hereditary cancer-predisposing syndrome	2015-11-12	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	RCV000202803	SCV000257606	uncertain significance	not specified	2015-07-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202803	SCV000694351	benign	not specified	2019-02-22	criteria provided, single submitter	clinical testing	Variant summary: ATM c.7390T>C (p.Cys2464Arg) results in a non-conservative amino acid change located in the PIK-related kinase, FAT domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00042 in 282084 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.00042 vs 0.001). However, this variant has been reported in 16/9884 (0.0016) women older than age 70 and cancer free. This frequency is higher than expected for a pathogenic variant in ATM causing Breast Cancer (0.0016 vs 0.001), suggesting this variant does not associate with cancer. c.7390T>C has been reported in the literature in individuals affected with Breast Cancer. These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic variants have been reported in our internal database (CHEK2 c.1100delC, p.Thr367fsX15; TP53 c.782+1G>T), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant. Seven 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 (1x Benign, 2 x Likely benign, 4x VUS). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000589438	SCV000780404	uncertain significance	not provided	2024-03-01	criteria provided, single submitter	clinical testing	ATM: PM2:Supporting
Color Diagnostics, LLC DBA Color Health	RCV000115249	SCV000910578	benign	Hereditary cancer-predisposing syndrome	2015-11-17	criteria provided, single submitter	clinical testing
Mendelics	RCV000119204	SCV001138562	uncertain significance	Ataxia-telangiectasia syndrome	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000119204	SCV001261060	uncertain significance	Ataxia-telangiectasia syndrome	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000589438	SCV001473046	likely benign	not provided	2019-10-31	criteria provided, single submitter	clinical testing
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000115249	SCV001911484	uncertain significance	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.7390T>C (p.Cys2464Arg) variant has an allele frequency of 0.00043 (0.04%, 114/268,152 alleles) in the gnomAD v2.1.1 non-cancer dataset, with a maximal frequency of 0.00092 (0.09%, 109/118,016 alleles) in the European (non-Finnish) subpopulation (BS1; http://gnomad.broadinstitute.org). This missense variant is not predicted to lead to a splicing alteration as per SPiCE predictor and no splicing site is created/activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer, but it alters the protein function / structure on the in-silico prediction reports of REVEL and PROVEAN (PP3). There is no other supporting data that meet criteria for consideration. Therefore, the clinical significance of this variant is uncertain. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: BS1 + PP3 (PMID: 33280026).
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000589438	SCV002010786	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798325	SCV002042887	uncertain significance	Breast and/or ovarian cancer	2023-03-09	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202803	SCV002070990	uncertain significance	not specified	2017-11-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115249	SCV002537670	likely benign	Hereditary cancer-predisposing syndrome	2021-06-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202803	SCV002760693	likely benign	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Revvity Omics, Revvity	RCV000119204	SCV003827470	uncertain significance	Ataxia-telangiectasia syndrome	2020-03-19	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549571	SCV004113598	uncertain significance	ATM-related disorder	2023-05-02	criteria provided, single submitter	clinical testing	The ATM c.7390T>C variant is predicted to result in the amino acid substitution p.Cys2464Arg. This variant has been identified in individuals with breast cancer (Table 1, Dörk et al. 2001. PubMed ID: 11606401; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682; Decker et al. 2017. PubMed ID: 28779002). This variant was also identified in an individual with colorectal cancer with deficient DNA mismatch repair activity, and who also had constitutional MLH1 promoter methylation (eTable 2, Pearlman et al. 2017. PubMed ID: 27978560). Functional in vitro and in vivo analysis showed that this variant had normal induction of ATM kinase activity, and potentially does not interfere with ATM function (Scott et al. 2002. PubMed ID: 11805335). This variant is reported in 0.091% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108201023-T-C) and has conflicting interpretations in ClinVar ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127443/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589438	SCV004222143	benign	not provided	2023-03-31	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356727	SCV001551971	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Cys2464Arg variant was identified in 25 of 16960 proband chromosomes (frequency: 0.002) from individuals or families with B chronic lymphocytic leukemia, breast cancer or pancreatic cancer and was present in 18 of 5488 control chromosomes (frequency: 0.003) from healthy individuals (Athanasakis 2014, Bernstein 2010, Decker 2017, Dork 2001, Grant 2015, Skowronska 2012, Tavtigian 2009). The variant was also identified in dbSNP (ID: rs55801750) as "With other allele", ClinVar (classified as Benign by Ambry Genetics; as likely benign by Invitae, GeneDx, and Integrated Genetics/Laboratory Corporation of America; as uncertain significance by four submitters), and in LOVD 3.0 (2x as unclassified variant). The variant was identified in control databases in 118 of 277014 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 3 of 24034 chromosomes (freq: 0.0001), Other in 1 of 6460 chromosomes (freq: 0.0002), European in 114 of 126536 chromosomes (freq: 0.0009), while the variant was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys2464 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Natera, Inc.	RCV000119204	SCV002080599	likely benign	Ataxia-telangiectasia syndrome	2020-02-14	no assertion criteria provided	clinical testing