Submissions for variant NM_000051.4(ATM):c.5185G>C (p.Val1729Leu)

gnomAD frequency: 0.00011  dbSNP: rs3092907

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000589866	SCV000149115	uncertain significance	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Observed in individuals with ataxia-telangiectasia, including one individual who also carried a homozygous pathogenic ATM variant and another who carried a heterozygous ATM pathogenic variant on the opposite allele (in trans) (PMID: 17124347, 29482223, 33779842); In silico analysis indicates that this missense variant does not alter protein structure/function; Observed in individuals with breast, colorectal, uterine, and prostate cancer (PMID: 28640387, 29522266, 29684080, 30303537, 33436325, 35264596, 35534704); This variant is associated with the following publications: (PMID: 11443540, 17124347, 22529920, 28640387, 29482223, 28652578, 29684080, 29522266, 19781682, 26689913, 30303537, 33203166, 33436325, 32522261, 35980532, 35264596, 37450374, 34482403, 33779842, 37745463, 35534704, 37529773)
Ambry Genetics	RCV000115206	SCV000185913	likely benign	Hereditary cancer-predisposing syndrome	2018-09-28	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	RCV000204511	SCV000261222	likely benign	Ataxia-telangiectasia syndrome	2024-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002307394	SCV000694300	uncertain significance	not specified	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5185G>C (p.Val1729Leu) results in a conservative amino acid change in 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 0.0001 in 251330 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.0001 vs 0.004), allowing no conclusion about variant significance. c.5185G>C has been reported in the literature as a "polymorphism" in a study of individuals affected with Ataxia-Telangiectasia, as a VUS in settings of multigene panel testing in an individual with a personal and/or family history of breast cancer and in unaffected controls (example, Magliozzi_2006, Tavtigian_2009, Pereira_2022). In one family the variant is reported to segregate with disease (example: Shalash_2021). However, these reports do not provide unequivocal conclusions about a penetrant association of the variant with Ataxia-Telangiectasia/ATM-related cancers. The following publications have been ascertained in the context of this evaluation (PMID: 22529920, 35264596, 33436325, 17124347, 35980532, 33779842, 19781682, 11443540). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (likely benign, n=4; VUS, n=8). Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics	RCV000204511	SCV000838552	likely benign	Ataxia-telangiectasia syndrome	2024-04-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115206	SCV000910687	likely benign	Hereditary cancer-predisposing syndrome	2016-11-04	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000589866	SCV001143111	uncertain significance	not provided	2020-01-20	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262810	SCV001440817	uncertain significance	Familial cancer of breast	2019-01-01	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000589866	SCV001469355	uncertain significance	not provided	2020-01-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00017 (6/35438 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with ataxia telangiectasia (AT) (PMID: 33779842 (2021), 17124347 (2006)) or cerebellar ataxia (PMID: 29482223 (2018)). It has also been reported in individuals with breast cancer (PMID: 33471991 (2021), 30303537 (2019), 29522266 (2018)), uterine cancer (PMID: 29684080 (2018)), prostate cancer (PMID: 33436325 (2021)), or colorectal cancer (PMID: 28640387 (2017)). This variant is also reported in individuals unaffected by cancer (PMID: 33471991 (2021), 28652578 (2017), FLOSSIES (http://whi.color.com/)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
Sema4, Sema4	RCV000115206	SCV002528320	likely benign	Hereditary cancer-predisposing syndrome	2021-01-08	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002307394	SCV004243447	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001262810	SCV005084069	likely benign	Familial cancer of breast	2024-05-22	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].
True Health Diagnostics	RCV000115206	SCV000787871	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-23	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000589866	SCV001550988	uncertain significance	not provided		no assertion criteria provided	clinical testing	The ATM p.Val1729Leu variant was identified in 3 of 9436 proband chromosomes (frequency: 0.0003) from individuals or families with cerebellar ataxia, Ataxia telangiectasia, and colorectal cancer, and was present in 2 of 4676 control chromosomes (frequency: 0.0004) from healthy individuals (Coutelier 2018, Magliozzi 2006, Ricker 2017, Tavtigian 2009, Thorstenson 2001). The variant was also identified in the following databases: dbSNP (ID: rs3092907) as "With Uncertain significance allele", ClinVar (1x likely benign, 3x uncertain significance), and Clinvitae. The variant was not identified in COGR, Cosmic, MutDB, LOVD 3.0, or ATM-LOVD. The variant was identified in control databases in 28 of 276848 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 6 of 6458 chromosomes (freq: 0.0009), Latino in 6 of 34416 chromosomes (freq: 0.0002), and European in 16 of 126392 chromosomes (freq: 0.0001); it was not observed in the African, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. Multiple studies list this variant as a polymorphism and one study found this variant co-occurring with the ATM homozygous pathogenic variant c.9022C>T (p.R3008C) (Magliozzi 2006, Thorstenson 2001, Coutelier 2018), increasing the likelihood this variant may not have clinical significance. The p.Val1729 residue is not 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589866	SCV001742385	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589866	SCV001959211	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000589866	SCV001965123	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000589866	SCV002034321	uncertain significance	not provided		no assertion criteria provided	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115206	SCV002506593	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-10	no assertion criteria provided	clinical testing
Genetic Services Laboratory, University of Chicago	RCV002307394	SCV003839214	uncertain significance	not specified	2022-07-14	no assertion criteria provided	clinical testing	DNA sequence analysis of the ATM gene demonstrated a sequence change, c.5185G>C, in exon 35 that results in an amino acid change, p.Val1729Leu. This sequence change has been described in the gnomAD database with a frequency of 0.017% in the Latino subpopulation (dbSNP rs3092907). The p.Val1729Leu change affects a moderately conserved amino acid residue located in a domain of the ATM protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Val1729Leu substitution. This sequence change has been reported in one individual with breast cancer (PMID: 30303537). It has also been detected in the homozygous state in one individual with a metabolic presentation ataxia (PMID: 29482223) and in trans with a pathogenic variant in a family with ataxia telangiectasia (PMID: 33779842). Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Val1729Leu change remains unknown at this time.
PreventionGenetics, part of Exact Sciences	RCV004739393	SCV005351743	uncertain significance	ATM-related disorder	2024-05-02	no assertion criteria provided	clinical testing	The ATM c.5185G>C variant is predicted to result in the amino acid substitution p.Val1729Leu. This variant was identified in the lymphoblastoid cell line of an individual affected with ataxia telangiectasia (Table 4, Magliozzi et al. 2006. PubMed ID: 17124347). Additionally, this variant has been reported in the homozygous state in an individual with cerebellar ataxia; however, that individual also had a homozygous pathogenic variant in ATM, suggesting this variant is less likely to be a primary cause of disease (Table e2 - Coutelier et al. 2018. PubMed ID: 29482223). This variant was also identified in at least two presumably healthy individuals (Thorstenson et al. 2001. PubMed ID: 11443540; Table S2, Tavtigian et al. 2009. PubMed ID: 19781682). This variant has been observed in ~0.1% of individuals in a population database and is reported in ClinVar with conflicting interpretations including likely benign and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127401/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.