ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.5185G>C (p.Val1729Leu) (rs3092907)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589866 SCV000149115 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.5185G>C at the cDNA level, p.Val1729Leu (V1729L) at the protein level, and results in the change of a Valine to a Leucine (GTT>CTT). This variant has been reported in at least two individuals with Ataxia-telangiectasia, including one individual with cerebellar ataxia who carried this variant in the homozygous state but was also found to carry a pathogenic ATM variant in the homozygous state (Magliozzi 2006, Coutelier 2018). ATM Val1729Leu has also been observed in individuals with breast, colorectal, or uterine cancer as well as in unaffected individuals (Thorstenson 2001, Ricker 2017, Tiao 2017, Hauke 2018, Yehia 2018). Additionally, ATM Val1729Leu was not seen in 4,112 breast cancer patients, but was identified in 1/2,399 control subjects in a large meta-analysis (Tavtigian 2009). This variant was observed at an allele frequency of 0.02% (6/34,416) in individuals of Latino ancestry in large population cohorts (Lek 2016). ATM Val1729Leu is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Val1729Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115206 SCV000185913 likely benign Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing Does not segregate with disease in family study (genes with incomplete penetrance);No disease association in small case-control study;Other data supporting benign classification
Invitae RCV000204511 SCV000261222 likely benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000589866 SCV000694300 uncertain significance not provided 2016-02-23 criteria provided, single submitter clinical testing Variant summary: c.5185G>C affects a conserved nucleotide, resulting in amino acid change from Val to Leu. 2/4 in-silico tools predict this variant to be benign (SNPs&GO not captured due to low reliability index). The variant is located 8 nucleotides from the inton/exon boundary of exon 35, however 5/5 in silico tools via Alamut predict no significant effect on canonical splicing site and 1/5 in silico tools predict loss of a cryptic splicing donor and acceptor sites. ESEfinder predicts a gain of binding motif for RNA splicing enhancer. These in silico predictions have not been validated by any in vivo/vitro functional studies. This variant was found in 10/121910 control chromosomes at a frequency of 0.0000000082, which does not significantly exceed the predicted maximal expected frequency of a pathogenic allele (0.0039528). The variant has not been reported in affected individuals in the literature, however has been reported in an unaffected control individuals and was considered as a polymorphism (Thorstenson_2001, Magliozzi_2006). Two reputable databases have classified the variant as "likely benign" and one classified this variant as VUS, all without evidence to independently evaluate. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS), until additional information becomes available.
Mendelics RCV000204511 SCV000838552 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115206 SCV000910687 likely benign Hereditary cancer-predisposing syndrome 2016-11-04 criteria provided, single submitter clinical testing
Athena Diagnostics Inc 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
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.

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