ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8147T>C (p.Val2716Ala) (rs587782652)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Academic Department of Medical Genetics, University of Cambridge RCV000132066 SCV000992207 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-26 criteria provided, single submitter research Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
Ambry Genetics RCV000132066 SCV000187129 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-14 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: in silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbSNP, ESP, 1000 Genomes),Other data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s)
Color RCV000132066 SCV000682458 likely pathogenic Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Counsyl RCV000169105 SCV000220304 likely pathogenic Ataxia-telangiectasia syndrome 2014-05-13 criteria provided, single submitter literature only
GeneDx RCV000212079 SCV000209770 pathogenic not provided 2018-04-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.8147T>C at the cDNA level, p.Val2716Ala (V2716A) at the protein level, and results in the change of a Valine to an Alanine (GTT>GCT). This variant has been observed in the compound heterozygous state in multiple individuals with atypical or later-onset ataxia telangiectasia (Hiel 2006, Verhagen 2009, Demuth 2011, Keimling 2011, M?neret 2014, Kuhm 2015, Lohmann 2015, van Os 2017). In addition, ATM Val2716Ala has been published in the heterozygous state in at least three individuals with early-onset breast cancer, one of whom also had a history of unexplained childhood onset choreoathetosis, oculocutaneous telangiectasias, and elevated serum alpha-fetoprotein (Mandigers 2011, Reiman 2011). Although this variant may express some level of kinase activity, it has been associated with reduced ATM protein expression, and transfected cells have exhibited reduced radiation-induced kinase activity (Scott 2002, Verhagen 2009, Demuth 2011, Reiman 2011). ATM Val2716Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the kinase domain and the ATP-binding domain (Lavin 2004, Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider ATM Val2716Ala to be pathogenic.
GeneReviews RCV000169105 SCV000328271 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000709709 SCV000839884 likely pathogenic Familial cancer of breast 2017-06-05 criteria provided, single submitter clinical testing This c.8147T>C (p.Val2716Ala) has previously been reported in compound heterozygous patients with ataxia telangiectasia most of them diagnosed in adulthood [PMID 19535770, 16864838, 21965147]. This variant is located in the kinase domain and in vitro data showed reduced kinase activity and lower ATM protein [PMID 11805335]. This variant was observed in 5 individuals at the heterozygous state in the ExAC database (http://exac.broadinstitute.org/variant/11-108205832-T-C). Valine at amino acid position 2716 of the ATM protein is conserved in mammals. While not validated for clinical use, computer-based algorithms SIFT and Polyphen-2 did not yield concordant predictions regarding the pathogenicity of the change. It is thus interpreted as a likely pathogenic variant. However, the estimated cancer risk for this variant has not been determined.
Integrated Genetics/Laboratory Corporation of America RCV000169105 SCV000918562 pathogenic Ataxia-telangiectasia syndrome 2018-09-10 criteria provided, single submitter clinical testing Variant summary: ATM c.8147T>C (p.Val2716Ala) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 277104 control chromosomes (gnomAD). The variant, c.8147T>C, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Demuth_2011, Hiel_2006, Lohmann_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Scott_2001). Five ClinVar submission from other clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000169105 SCV000260088 pathogenic Ataxia-telangiectasia syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 2716 of the ATM protein (p.Val2716Ala). The valine residue is highly conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs587782652, ExAC 0.02%). This variant has been reported in several individuals affected with ataxia-telangiectasia (A-T) (PMID: 16864838, 19535770, 21354641, 21965147), as well as in an individual with generalized dystonia (PMID: 2557216), and an individual with breast cancer (PMID: 26976419). This variant has been reported to segregate with another pathogenic variant in ATM in a single family with dystonia (PMID: 25957637). ClinVar contains an entry for this variant (Variation ID: 142700). Experimental studies have shown that this missense change reduces ATM kinase activity and increases radiosensitivity (PMID: 11805335). For these reasons, this variant has been classified as Pathogenic.

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