ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8565_8566delinsAA (p.Ser2855_Val2856delinsArgIle) (rs587781353)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129137 SCV000183858 likely pathogenic Hereditary cancer-predisposing syndrome 2013-11-19 criteria provided, single submitter clinical testing
Color RCV000129137 SCV000682500 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-04 criteria provided, single submitter clinical testing
GeneDx RCV000235111 SCV000209611 likely pathogenic not provided 2018-11-28 criteria provided, single submitter clinical testing This variant is denoted ATM c.8565_8566delTGinsAA at the DNA level and p.Ser2855_Val2856delinsArgIle (S2855_V2856delinsRI) at the protein level. The surrounding sequence is GCAG[delTG][insAA]TAGC. The deletion and insertion results in the replacement of two amino acids (a Serine and a Valine) with two others (an Arginine and an Isoleucine), creating two adjacent missense changes: Ser2855Arg and Val2856Ile. ATM c.8565_8566delTGinsAA was not observed in large population cohorts (Lek 2016). This variant is located within the catalytic region of the kinase domain (Lavin 2004, Stracker 2013). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. This combined variant has been reported in at least two women with breast cancer and in a patient with Ataxia-telangiectasia (Hacia 1998, Tavtigian 2009, Dosani 2017). Furthermore, a functional study showed reduced levels of ATM protein and absent kinase activity (Barone 2009). Based on current evidence, we consider ATM c.8565_8566delTGinsAA to be a likely pathogenic variant.
Invitae RCV000456994 SCV000547074 likely pathogenic Ataxia-telangiectasia syndrome 2018-12-04 criteria provided, single submitter clinical testing This variant, c.8565_8566delinsAA, is a complex sequence change that results in the deletion of 2 amino acids (Ser2855_Val2856) and insertion of 2 amino acids (Arg, Ile) in the ATM protein (p.Ser2855_Val2856delinsArgIle). This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with ataxia-telangiectasia (A-T) (PMID: 9872980, 8659541, 10817650). A second pathogenic variant (6015insC) was detected in one of these individuals (PMID: 9872980, 8659541). It has also been observed in individuals with breast cancer (PMID: 19781682, 26681312, 28929041). ClinVar contains an entry for this variant (Variation ID: 140897). Experimental studies have shown that this sequence change disrupts ATM kinase activity in vitro. It also caused increased radiosensitivity in a transformed lymphoblastoid cell line (PMID: 19431188, 11857346). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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