Submissions for variant NM_000051.4(ATM):c.4388T>G (p.Phe1463Cys)

gnomAD frequency: 0.00103  dbSNP: rs138327406

Total submissions: 23

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000120139	SCV000149102	benign	not specified	2017-05-26	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	RCV000122848	SCV000166106	benign	Ataxia-telangiectasia syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115193	SCV000183891	benign	Hereditary cancer-predisposing syndrome	2014-06-19	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.
Eurofins Ntd Llc (ga)	RCV000588436	SCV000228685	uncertain significance	not provided	2015-02-05	criteria provided, single submitter	clinical testing
Vantari Genetics	RCV000115193	SCV000266992	uncertain significance	Hereditary cancer-predisposing syndrome	2015-10-26	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000120139	SCV000593483	likely benign	not specified	2019-11-26	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000588436	SCV000602567	likely benign	not provided	2023-08-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115193	SCV000682201	benign	Hereditary cancer-predisposing syndrome	2014-12-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000588436	SCV000694279	likely benign	not provided	2016-05-09	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.4388T>G (p.Phe1463Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, these predictions have not been validated by any in vitro/vivo functional studies. This variant was found in 172/120622 control chromosomes (3 homozygotes) at a frequency of 0.0014259, which is approximately 3 times the estimated maximal expected allele frequency of a pathogenic ATM variant for breast cancer (0.0005001), suggesting this variant does not cause breast cancer. The variant was found in 149/65460 European non-Finnish chromosomes (0.002276) with 3 homozygotes; while this frequency does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant for Ataxia-telangiectasia (AT; 0.0039528), AT is a childhood disorder, and thus it would be unlikely for there to be 3 homozygous unaffected individuals in the ExAC database. Furthermore, it has been shown that while heterozygotes are not at increased risk of developing A-T neurologic manifestations, they have a fourfold increased risk of developing breast cancer through mechanisms that are not understood. Thus, if this were a pathogenic AT-causing variant, it would increase the risk of breast cancer. However, population control data strongly indicate that this variant does not cause breast cancer.This variant has been reported in patients with a variety types of cancers such as BrC, HD, HBOC, B-CLL, OvC, Pancreatic Cancer, and hemangioblastomas, however, there was no strong evidence to support the causative correlation of this variant with the diseases. Additionally, the variant was found to co-occur with likely pathogenic variants (BRIP1 c.440dupA and ATM c.1027_1030delGAAA) in internal specimens tested for cancer risk.Two clinical laboratories (via ClinVar) classified this variant as benign, one classified this variant as likely benign, and two labs classified it as VUS, without evidence to independently evaluate. Considering all, the variant was classified as Likely Benign until additional information becomes available.
Counsyl	RCV000122848	SCV000797992	likely benign	Ataxia-telangiectasia syndrome	2018-02-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000120139	SCV000805563	benign	not specified	2017-05-30	criteria provided, single submitter	clinical testing
Mendelics	RCV000122848	SCV000838538	likely benign	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000588436	SCV000840940	benign	not provided	2017-11-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000588436	SCV001249804	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	ATM: BS2
Illumina Laboratory Services, Illumina	RCV000122848	SCV001263903	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.
Sema4, Sema4	RCV000115193	SCV002534701	benign	Hereditary cancer-predisposing syndrome	2020-06-10	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000120139	SCV002773997	benign	not specified	2022-02-16	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000120139	SCV004027224	likely benign	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004589565	SCV005083987	likely benign	Familial cancer of breast	2024-05-17	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].
ITMI	RCV000120139	SCV000084279	not provided	not specified	2013-09-19	no assertion provided	reference population
Natera, Inc.	RCV000122848	SCV001462144	benign	Ataxia-telangiectasia syndrome	2020-04-17	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356026	SCV001551080	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The ATM p.Phe1463Cys variant was identified in 12 of 4036 proband chromosomes (frequency: 0.00297) from individuals or families with breast cancer, ovarian cancer, Non-Hodgkin's lymphoma and Lynch syndrome (Liberzon 2004, Maillet 2002, Stafford 2017, Tung 2016, Yorczyk 2015, Yurgelun 2015). The variant was also identified in dbSBP (ID: rs138327406) as “With other allele”, ClinVar 6x with conflicting interpretations of pathogenicity (as uncertain significance by EGL Genetic and Vantari Genetics, as likely benign by GeneDx, and as benign by Invitae and Ambry Genetics), Clinvitae (4x), and Cosmic databases. The variant was not identified in MutDB, LOVD 3.0, and ATM-LOVD databases. The variant was identified in control databases in 405 of 276966 chromosomes at a frequency of 0.001462 in the following populations: Ashkenazi Jewish in 274 (7 homozygous) of 10144 chromosomes (freq. 0.027), Other in 21 of 6456 chromosomes (freq. 0.0033), Latino in 35 of 34392 chromosomes (freq. 0.001), European (Non-Finnish) in 67 of 126564 chromosomes (freq. 0.0005) and African in 8 of 24014 (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The p.Phe1463Cys variant was found to co-occur with p.Pro604Ser in 2 individuals with Non-Hodgkin’s lymphoma (Liberzon 2004). One study concluded that the p.Phe1463Cys variant is pathogenic in breast cancer because the amino acid substitution is known to be deleterious to ATM function in patients with B cell non-Hodgkin’s lymphomas, as well as based on conservation data (Maillet 2002). The p.Phe1463 residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115193	SCV001950164	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	no assertion criteria provided	clinical testing