ClinVar Miner

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

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Total submissions: 6
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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 2019-04-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
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 likely benign Ataxia-telangiectasia syndrome 2019-12-30 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
Color RCV000131552 SCV000902980 likely benign Hereditary cancer-predisposing syndrome 2016-04-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001199851 SCV001370583 uncertain significance not specified 2020-05-26 criteria provided, single submitter clinical testing Variant summary: ATM c.1464G>T (p.Trp488Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251336 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1464G>T has been reported in the literature in sequencing studies of individuals affected with Breast and other types of cancer (example, Castera_2014, Yorczyk_2015, Young_2016, Tavera-Tapia_2017, Renault_2018, Momozawa_2018, Girard_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (VUS, n=3; likely benign, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.

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