ClinVar Miner

Submissions for variant NM_001330368.2(C11orf65):c.641-23784_641-23780del (rs1450394308)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222650 SCV000273655 pathogenic Hereditary cancer-predisposing syndrome 2017-01-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000003171 SCV000486550 pathogenic Ataxia-telangiectasia syndrome 2016-10-19 criteria provided, single submitter clinical testing
Invitae RCV000003171 SCV000547031 pathogenic Ataxia-telangiectasia syndrome 2018-12-17 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides in exon 53 of the ATM mRNA (c.7886_7890delTATTA), causing a frameshift at codon 2629. This creates a premature translational stop signal (p.Ile2629Serfs*25) and is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic. This particular variant has been reported in the literature as homozygous or compound heterozygous in individuals with ataxia-telangiectasia (PMID: 12815592, 23322442, 8845835, 23946315, 9600235). This variant has also been reported in individuals with breast cancer and/or ovarian cancer (PMID: 21787400, 26436112). This variant is also known as 7883del5, 7884_7888del5, c.7878_7882delTTATA and c.7886_7890del. For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000483952 SCV000568334 pathogenic not provided 2018-10-22 criteria provided, single submitter clinical testing This deletion of five nucleotides in ATM is denoted c.7886_7890delTATTA at the cDNA level and p.Ile2629SerfsX25 (I2629SfsX25) at the protein level. The normal sequence, with the bases that are deleted in brackets, is ATTA[delTATTA]GCAA. The deletion causes a frameshift which changes an Isoleucine to a Serine at codon 2629, and creates a premature stop codon at position 25 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.7886_7890delTATTA, previously reported as 7883del5, 7884_7888del5, 7878del5, and 7886_7889del5, has been observed in both the homozygous and compound heterozygous state in patients with Ataxia-telangiectasia and in at least one individual with breast cancer (Gilad 1996, Ejima 1998, Mitui 2003, Exley 2011, Goldgar 2011, Charlesworth 2013, Jeddane 2013). We consider this variant to be pathogenic.
Color RCV000222650 SCV000682440 pathogenic Hereditary cancer-predisposing syndrome 2017-02-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000003171 SCV000694361 pathogenic Ataxia-telangiectasia syndrome 2017-05-25 criteria provided, single submitter clinical testing Variant summary: The ATM c.7886_7890delTATTA (p.Ile2629Serfs) variant (also known as 7878del5, 7883del5 and 7884_7888del5) 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. p.Lys2756X, p.Arg2763X, p.Arg2993X, etc.). This variant is absent in 120872 control chromosomes from ExAC. This variant has been reported in several A-T patients/families across multiple countries in homozygous state as well as in compound heterozygous state with other pathogenic/likely pathogenic variants (Gilad_1996, Telatar_1996, Sasaki_1998, Stankovic_1998, Exley_2011, Mitui_2003, Jeddane_2013, Charlesworth_2013). Cosegregation of this variant with disease have also been reported from a family (Charlesworth_2013). It has also been found in a breast cancer patient (Hirotsu_2015), which is consistent with the fact that pathogenic variants in ATM gene are known to confer elevated risk of breast cancer in a heterozygous state. In a compound heterozygous patient that carried this variant and 3802delG, no ATM kinase activity and ATM protein expression was observed in lymphoblastoid cell line derived from the patient, strongly supporting its predicted outcome (Exley_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mendelics RCV000003171 SCV000838601 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
OMIM RCV000003171 SCV000023329 pathogenic Ataxia-telangiectasia syndrome 1998-04-01 no assertion criteria provided literature only
GeneReviews RCV000003171 SCV000328270 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only

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