ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8071C>T (p.Arg2691Cys) (rs531980488)

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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 RCV000131504 SCV000186493 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Color RCV000131504 SCV000682453 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-15 criteria provided, single submitter clinical testing
Counsyl RCV000199628 SCV000791912 uncertain significance Ataxia-telangiectasia syndrome 2017-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000587628 SCV000568336 uncertain significance not provided 2018-10-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.8071C>T at the cDNA level, p.Arg2691Cys (R2691C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been observed in individuals with breast cancer, chronic lymphocytic leukemia, and thyroid cancer (Sommer 2003, Guarini 2012, Heikkinen 2005, Tavtigian 2009, Yu 2015, Xie 2017). ATM Arg2691Cys was also identified in 1/62 healthy East Asian individuals undergoing whole genome sequencing (Bodian 2014) and in 1/2399 individuals without a personal history of breast cancer (Tavtigian 2009). Of note, the participants in the Bodian et al. (2014) study were younger than 50 years old thus the unaffected status of this individual may not be significant. In addition, ATM Arg2691Cys was observed at an allele frequency of 0.064% (11/17,228) in individuals of East Asian ancestry in large population cohorts (Lek 2016). ATM Arg2691Cys 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 Arg2691Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000120161 SCV000084303 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000587628 SCV000694370 uncertain significance not provided 2016-05-16 criteria provided, single submitter clinical testing Variant summary: The ATM c.8071C>T (p.Arg2691Cys) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). However, they are not definitive and there are no published functional studies for the variant. This variant was found in 14/123436 control chromosomes at a frequency of 0.0001134, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0005001). The population data, however, may still suggest it is a very rare polymorphism. It has been reported in multiple breast cancer patients, however without strong evidence for or against pathogenicity. In one patient with leukemia, another cytogenetic abnormality 'deletion 13q14' was also detected (Guarini_2012), suggesting that the variant was not the cause of the disease. The variant has not been detected in A-T patient, to our knowledge. Two clinical labs in ClinVar have classified it as having uncetain significance, however without evidence to independently evaluate. One internal sample carrying this variant also carried PALB2 p.L484X variant, suggesting a possible benign outcome. These population, clinical and internal data suggests that it is unlikely to cause breast cancer. Taken together, considering the breast cancer as phenotype, it has been classified as VUS-possibly Benign.
Invitae RCV000199628 SCV000254153 uncertain significance Ataxia-telangiectasia syndrome 2018-11-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2691 of the ATM protein (p.Arg2691Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs531980488, ExAC 0.07%). This variant has been reported in case-control studies, where it was observed in several individuals affected with breast cancer and an unaffected individual (PMID: 12935922, 15756685, 19781682, 20305132). This variant has also been reported in individuals affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 133636). 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: "Possibly Damaging"; 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.
Mendelics RCV000199628 SCV000838606 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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