ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2522A>C (p.Asp841Ala) (rs587781812)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163825 SCV000214411 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000205271 SCV000261914 uncertain significance Ataxia-telangiectasia syndrome 2020-01-06 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with alanine at codon 841 of the ATM protein (p.Asp841Ala). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and alanine. This variant is present in population databases (rs587781812, ExAC 0.2%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 29470806,26689913, 26911350). ClinVar contains an entry for this variant (Variation ID: 184552). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C15"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000589287 SCV000566199 uncertain significance not provided 2018-08-21 criteria provided, single submitter clinical testing This variant is denoted ATM c.2522A>C at the cDNA level, p.Asp841Ala (D841A) at the protein level, and results in the change of an Aspartic Acid to an Alanine (GAT>GCT). This variant has been observed in at least two breast and/or ovarian cancer patients (Lu 2015, Mannan 2016). ATM Asp841Ala was observed at an allele frequency of 0.143% (44/30,780) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Asp841Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Fulgent Genetics,Fulgent Genetics RCV000515444 SCV000611352 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Color RCV000163825 SCV000682062 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589287 SCV000694228 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The ATM c.2522A>C (p.Asp841Ala) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant is not located in any known domain (InterPro). This variant was found in 31/121120 control chromosomes (1 homozygote), predominantly observed in the South Asian subpopulation at a frequency of 0.0018845 (31/16450). This frequency is about 1.9 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is possibly a benign polymorphism found primarily in the populations of South Asian origin. This variant has also been reported in two patients with breast or ovarian cancer without strong evidence for pathogenicity (i.e. co-segregation). In addition, multiple clinical diagnostic laboratories have classified this variant as uncertain significance. Taken together, this variant is currently classified as Variant of Uncertain Significance Possibly Benign.
PreventionGenetics,PreventionGenetics RCV000589287 SCV000805520 likely benign not provided 2017-11-10 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000589287 SCV000840927 likely benign not provided 2018-10-29 criteria provided, single submitter clinical testing

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