ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6820G>A (p.Ala2274Thr) (rs567060474)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000159644 SCV000215124 likely benign Hereditary cancer-predisposing syndrome 2017-08-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000159644 SCV000910700 likely benign Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000588200 SCV000705521 uncertain significance not provided 2017-02-17 criteria provided, single submitter clinical testing
GeneDx RCV000588200 SCV000209633 uncertain significance not provided 2018-08-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.6820G>A at the cDNA level, p.Ala2274Thr (A2274T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). ATM Ala2274Thr was observed at an allele frequency of 0.02% (25/126,368) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the FAT domain (Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. This variant has been observed in individuals with breast cancer, pancreatic cancer, rectal cancer, multiple myeloma, and chronic lymphocytic leukemia (Dork 2001, Scott 2002, Austen 2008, Broeks 2008, Tavtigian 2009, Skowronska 2011, Navrkalova 2013, Li 2015, Yang 2016, Pearlman 2017, Renault 2018), with some individuals also harboring a second ATM missense variant, Arg1575His. However, ATM Ala2274Thr showed incomplete segregation with breast cancer and was present in unaffected women in two families (Thorstenson 2003). Functional studies in support of a neutral classification demonstrated protein expression, kinase activity, ability to correct the radiosensitive phenotype of A-T cell lines, and levels of radiation-induced chromosome aberrations comparable to wild-type (Scott 2002, Barone 2009). Suggesting possible pathogenicity or unknown significance, other functional studies demonstrated reduction in protein expression and function (Stankovic 1999, Navrkalova 2013). Of note, Navrkalova et al. (2013) observed ATM Ala2274Thr and Arg1575His in the germline of an individual with CLL whose leukemic cells also harbored ATM Gln984Glu and an 11q chromosomal deletion as somatic alterations, and total ATM function was only reported from the leukemic cells analyzed. Based on currently available evidence, it is unclear whether ATM Ala2274Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588200 SCV000694333 uncertain significance not provided 2016-04-25 criteria provided, single submitter clinical testing Variant summary: The c.6820G>A variant affects a conserved nucleotide, resulting in amino acid change from Ala to Thr. 4/4 in-silico tools predict damaging outcome for this variant. This variant is found in 13/123678 control chromosomes including the large and broad populations of ExAC at a frequency of 0.0001051, which does not exceed maximal expected frequency of a pathogenic allele (0.0005001) in this gene based on the disease prevalence of HBOC. This variant has been reported in literature in patients with breast cancer (at least 5 patients), multiple myeloma (n=1) and at least 2 patients with chronic lymphocytic leukemia ((Stankovic_1999, Dork_2001, Thorstenson_2003, Austen_2008, Broeks_2008, Tavtigian_2009, Skowronska_2011, Navrkalova_2012, Li_2016). In two reported HBOC families (Thorstenson_2003), this variant did not cosegregate with disease, suggesting a notion that it does not cause HBOC. However, the variants role as risk cannot be ruled out as the variant was found in another meta-analysis to be overrepresented in patient population than in control population (Tavtigian_2009). Functional studies are in support of a benign outcome as demonstrated by protein expression, kinase activity, and radiation-induced chromosome aberrations assays (Scott 2002, Barone 2009). However, it may have a function that is not measured in these assays. In addition, reduction in protein expression and function was shown in patients carrying this variant (Stankovic 1999, Navrkalova 2012), suggesting a possible pathogenicity or unknown significance. The variant has not been found in A-T patients. Three clinical laboratories in ClinVar classify the variant to have uncertain significance. Taken together, this variant has currently been classified as a Variant of Unknown Significance.
Invitae RCV000122880 SCV000166138 likely benign Ataxia-telangiectasia syndrome 2017-12-21 criteria provided, single submitter clinical testing
Mendelics RCV000122880 SCV000838580 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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