ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.275A>C (p.Lys92Thr) (rs200151849)

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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 RCV000165208 SCV000215920 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-05 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000205193 SCV000260296 uncertain significance Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces lysine with threonine at codon 92 of the ATM protein (p.Lys92Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is present in population databases (rs200151849, ExAC 0.1%). This variant has been observed in several individuals affected with breast cancer (PMID: 28580595, 30287823) and in several unaffected individuals (PMID: 30287823). ClinVar contains an entry for this variant (Variation ID: 133625). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 RCV000656755 SCV000564605 uncertain significance not provided 2017-12-26 criteria provided, single submitter clinical testing This variant is denoted ATM c.275A>C at the cDNA level, p.Lys92Thr (K92T) at the protein level, and results in the change of a Lysine to a Threonine (AAA>ACA). This variant was also identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. ATM Lys92Thr was observed at an allele frequency of 0.11% (19/18,844) in individuals of East Asian ancestry in large population cohorts (Lek 2016). ATM Lys92Thr is located in region of interaction with p53 & BRCA1 (Stracker 2013). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether ATM Lys92Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000165208 SCV000682074 likely benign Hereditary cancer-predisposing syndrome 2019-12-19 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764932 SCV000896104 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120147 SCV000918508 uncertain significance not specified 2017-10-06 criteria provided, single submitter clinical testing Variant summary: The c.275A>C (p.Lys92Thr) in ATM gene is a missense variant involves a conserved nucleotide and 3/4 in silico tools predict deleterious outcome. Although, the variant is located within the TAN motif that is essential for both telomere length maintenance and Tel1 action in response to DNA damage, no functional studies confirming an effect of this change on the protein function were published at the time of evaluation. In addition, based on the conservation alignment, the change could be tolerated. The variant is present in the control population datasets of ExAC and gnomAD (7.657e-05; 9/117540 and 0.000068; 19/276920 chrs tested, respectively), exclusively in individuals of East Asian descent (0.0010). The individual frequencies are similar to the maximal expected allele frequency for a disease causing allele in ATM gene (0.001), suggesting that this variant may represent a rare ethnic polymorphism. The variant has not, to our knowledge, been reported in affected individuals via published reports but is cited by several reputable databases/clinical laboratories as VUS. Taken together, the variant was classified as VUS-Possibly Benign, until new information becomes available.
Illumina Clinical Services Laboratory,Illumina RCV000205193 SCV001260302 uncertain significance Ataxia-telangiectasia syndrome 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
ITMI RCV000120147 SCV000084288 not provided not specified 2013-09-19 no assertion provided reference population

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