Submissions for variant NM_000051.4(ATM):c.4414T>G (p.Leu1472Val)

gnomAD frequency: 0.00009  dbSNP: rs539676759

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000588453	SCV000149104	likely benign	not provided	2020-12-23	criteria provided, single submitter	clinical testing	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with ATM-related and other cancers; however, in one patient a BRCA2 frameshift variant was also identified (Bernstein 2010, Yurgelun 2015, Decker 2017, Paulo 2018, Yehia 2018, Snow 2019); This variant is associated with the following publications: (PMID: 25980754, 28779002, 29659569, 27588518, 30309722, 30303537, 21787400, 20305132, 29684080, 31227566)
Ambry Genetics	RCV000115195	SCV000216988	likely benign	Hereditary cancer-predisposing syndrome	2023-01-10	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	RCV000206408	SCV000261255	likely benign	Ataxia-telangiectasia syndrome	2024-01-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115195	SCV000292154	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 1472 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 20305132, 33606809) and Lynch syndrome-associated cancer and/or polyps (PMID: 25980754). In a large international case-control study, this variant was reported in 9/60457 breast cancer cases and 5/53456 controls (PMID: 33471991). This variant has also been identified in 24/282146 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Fulgent Genetics, Fulgent Genetics	RCV000515407	SCV000611363	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002509222	SCV000694282	uncertain significance	not specified	2022-12-05	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4414T>G (p.Leu1472Val) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 250738 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Breast Cancer (7.6e-05 vs 0.001), allowing no conclusion about variant significance. c.4414T>G has been reported in the literature in individuals affected with breast cancer, prostate cancer, and other forms of cancer, as well as those being tested for Lynch syndrome (example, Bernstein_2010, Yurgelun_2015, Goldgar_2011, Girad_2019, Paulo_2018, Snow_2019). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer/ATM-related cancers/Ataxia Telangiectasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (likely benign, n=3, VUS, n=7). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV003492458	SCV000838541	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Division of Medical Genetics, University of Washington	RCV001257473	SCV001434279	uncertain significance	Familial cancer of breast	2019-10-08	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in individuals with different types of cancer, including breast cancer (Bernstein 2010, Yurgelun 2015, Decker 2017, Yehia 2018). This variant has an overall allele frequency of 0.00008 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate that this variant may not alter protein structure/function. Thus, it is unknown at this time whether this variant increases cancer risk. BP4
National Health Laboratory Service, Universitas Academic Hospital and University of the Free State	RCV002225319	SCV002504714	likely benign	Hereditary breast ovarian cancer syndrome	2022-04-19	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115195	SCV002534723	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-09	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588453	SCV002774769	uncertain significance	not provided	2022-08-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002509222	SCV004027226	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001257473	SCV005082031	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].
PreventionGenetics, part of Exact Sciences	RCV004739392	SCV000805564	uncertain significance	ATM-related disorder	2024-03-20	no assertion criteria provided	clinical testing	The ATM c.4414T>G variant is predicted to result in the amino acid substitution p.Leu1472Val. This particular variant has also been reported in individuals with suspected Lynch syndrome (Yurgelun et al. 2015. Table S2, PubMed ID: 25980754) and breast cancer (Girard. 2019. PubMed ID: 30303537, Supplementary Table S3; Goldgar et al. 2011. Table S1, PubMed ID: 21787400), although the latter study did not find significant association with increased breast cancer risk. This variant is reported in 0.037% of alleles in individuals of Latino descent in gnomAD. It has conflicting interpretations of likely benign and uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127390/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect - Invitae Patient Insights Network	RCV000588453	SCV001749402	not provided	not provided		no assertion provided	phenotyping only	Variant interpreted as Likely benign and reported on 05-27-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000588453	SCV001905734	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000588453	SCV001957550	uncertain significance	not provided		no assertion criteria provided	clinical testing