ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8266A>T (p.Lys2756Ter) (rs371638537)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122886 SCV000166144 pathogenic Ataxia-telangiectasia syndrome 2019-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 2756 (p.Lys2756*) of the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs371638537, ExAC 0.002%). This variant has been observed in individuals affected with ataxia-telangiectasia (A-T) (PMID: 10330348, 12552559, 8659541, 9463314), chronic lymphocytic leukemia (PMID: 11756185, 21933854), medulloblastoma (PMID: 28007021), pancreatic cancer (PMID: 22585167), breast cancer and prostate cancer (PMID: 26094658, 25503501, 26681312). ClinVar contains an entry for this variant (Variation ID: 135780). Experimental studies have shown that reprogrammed A-T cells carrying this variant exhibit partially disrupted ATM protein function, such as defective repair of DNA double-strand breaks and repressed phosphorylation of ATM substrates (PMID: 25032865). Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000128904 SCV000172765 pathogenic Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
GeneDx RCV000212082 SCV000209653 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.8266A>T at the cDNA level and p.Lys2756Ter (K2756X) at the protein level. The substitution creates a nonsense variant, changing a Lysine to a premature stop codon (AAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with ataxia-telangiectasia, chronic lymphocytic leukemia, colorectal cancer, and familial pancreatic cancer (Telatar 1996, Stankovic 1998, Teraoka 1999, Yuille 2002, Buzin 2003, Kato 2006, Du 2008, Skowronska 2012, Roberts 2012, Schrader 2015, Vanderver 2016). ATM Lys2756Ter has also been observed in individuals with familial breast cancer and prostate cancer (Maxwell 2014, Desmond 2015, Pritzlaff 2017). We therefore consider this variant to be pathogenic.
Counsyl RCV000122886 SCV000220141 likely pathogenic Ataxia-telangiectasia syndrome 2014-03-04 criteria provided, single submitter literature only
Color RCV000128904 SCV000682472 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000122886 SCV000694375 pathogenic Ataxia-telangiectasia syndrome 2016-08-11 criteria provided, single submitter clinical testing Variant summary: The ATM c.8266A>T (p.Lys2756X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.8264_8268delATAAG/p.Tyr2755fsX12). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/118602 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant has been reported in multiple patients with AT and different types of cancers. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics RCV000122886 SCV000807217 pathogenic Ataxia-telangiectasia syndrome 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a deleterious intronic mutation in a 7-month-old female with immune deficiency, hearing loss, and skin lesion.

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