ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1464G>T (p.Trp488Cys) (rs377597949)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131552 SCV000186553 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000131552 SCV000902980 likely benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515383 SCV000611343 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000235099 SCV000209776 uncertain significance not provided 2018-10-03 criteria provided, single submitter clinical testing This variant is denoted ATM c.1464G>T at the cDNA level, p.Trp488Cys (W488C) at the protein level, and results in the change of a Tryptophan to a Cysteine (TGG>TGT). This variant has been observed in individuals with breast cancer and in healthy controls (Tavtigian 2009, Decker 2017, Renault 2018). It has also been reported in individuals with histories suggestive of Hereditary Breast and Ovarian Cancer or who otherwise met hereditary cancer genetic testing criteria (Castera 2014, Yorczyk 2015, Tavera-Tapia 2017). ATM Trp488Cys was not observed at a significant allele frequency 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 Trp488Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000168391 SCV000219084 uncertain significance Ataxia-telangiectasia syndrome 2018-12-24 criteria provided, single submitter clinical testing This sequence change replaces tryptophan with cysteine at codon 488 of the ATM protein (p.Trp488Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. This variant is present in population databases (rs377597949, ExAC 0.004%). This variant has been reported in individuals with a personal and/or family history of breast or ovarian cancer (PMID: 24549055, 29665859), and in an individual undergoing genetic testing for hereditary cancers (PMID: 25318351). ClinVar contains an entry for this variant (Variation ID: 142433). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. 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.

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