ClinVar Miner

Submissions for variant NM_001330368.2(C11orf65):c.641-22822_641-22814del (rs587776547)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000185637 SCV000186502 pathogenic Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Other strong data supporting pathogenic classification;Deficient protein function in appropriate functional assay(s);Detected in individual(s) satisfying established diagnostic criteria for classic disease in trans with a mutation or mutation is homozygous;Rarity in general population databases (dbsnp, esp, 1000 genomes);Deficient protein function by in vitro/ex vivo assay
GeneDx RCV000212075 SCV000209607 pathogenic not provided 2018-08-29 criteria provided, single submitter clinical testing This deletion of nine nucleotides in ATM is denoted c.7638_7646delTAGAATTTC at the cDNA level and p.Arg2547_Ser2549del at the protein level. The normal sequence, with the bases that are deleted in braces, is TCTC{TAGAATTTC}AATG. This in frame deletion is located within the FAT domain (Stracker 2013, UniProt). This variant, also known as 7636del9 by alternate nomenclature, was observed in both the homozygous and compound heterozygous state in multiple individuals with classic Ataxia-telangiectasia (Byrd 1996, Wright 1996, Watters 1997, Stankovic 1998). Multiple functional analyses have confirmed the pathogenicity of this variant, showing complete absence of kinase activity and reduced ATM protein expression (Stewart 2001, Barone 2009, Reiman 2011). Based on current information, we consider this variant to be pathogenic.
Invitae RCV000206671 SCV000262210 pathogenic Ataxia-telangiectasia syndrome 2020-01-12 criteria provided, single submitter clinical testing This sequence change deletes 9 nucleotides from exon 52 of the ATM mRNA (c.7638_7646delTAGAATTTC). This leads to the deletion of 3 amino acid residues in the ATM protein (p.Arg2547_Ser2549del) but otherwise preserves the integrity of the reading frame. The frequency data for this variant (rs587776547) in the population databases is unreliable, as metrics indicate poor quality at this position in the ExAC database. This variant has been reported as homozygous and compound heterozygous in individuals affected with ataxia-telangiectasia, as well as heterozygous in individuals with breast cancer (PMID: 7792600, 12552559, 22649200, 11382771, 8797579, 21787400). This variant is also known as 7636del9 and 7638del9 in the literature. ClinVar contains an entry for this variant (Variation ID: 3019). Experimental studies have shown that this deletion disrupts ATM kinase function and leads to impaired cellular response to ionizing radiation (PMID: 19431188, 22649200, 11382771, 12195425). For these reasons, this variant has been classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000212075 SCV000331662 pathogenic not provided 2016-08-31 criteria provided, single submitter clinical testing
Counsyl RCV000206671 SCV000487009 pathogenic Ataxia-telangiectasia syndrome 2016-09-26 criteria provided, single submitter clinical testing
Color RCV000185637 SCV000682427 pathogenic Hereditary cancer-predisposing syndrome 2020-02-23 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000212075 SCV000805616 pathogenic not provided 2016-06-24 criteria provided, single submitter clinical testing
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000709706 SCV000839880 likely pathogenic Familial cancer of breast 2017-04-03 criteria provided, single submitter clinical testing This c.7638_7646del (p.Arg2547_Ser2549del) has previously been reported in compound heterozygous and homozygous patients with ataxia telangiectasia [PMID 8808599]. Functional assays showed that the variant does not affect the level of ATM protein but does reduce the level of kinase activity [PMID 19431188]. A mouse model carrying this deletion has an increase susceptibility to develop tumors [reported as 7636del9 in PMID 12195425]. This variant was further detected in 12 out of 294 families with breast cancer. However, the difference in tumor incidence between carrier and non carrier was not statistically significant. However, this variant was detected in another patient with breast cancer [PMID 8797579]. This c.7638_7646del (p.Arg2547_Ser2549del) variant has not been observed the ExAC population database and has been observed in one individual in our internal database. It is thus interpreted as a likely pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000206671 SCV000916557 pathogenic Ataxia-telangiectasia syndrome 2017-10-27 criteria provided, single submitter clinical testing Variant summary: The ATM c.7638_7646delTAGAATTTC (p.Arg2547_Ser2549del) variant involves the inframe deletion of 9 nucleotides located in the PIK-related kinase domain (IPR014009) (InterPro). One in silico tool predicts a damaging outcome for this variant. Functional studies confirmed that there is no detectable ATM kinase activity associated with this variant and that LCLs with this variant exhibited p53, p21, and MDM2 response that was indistinguishable from classical A-T (Stewart_2001). This variant was found in 5/246251 control chromosomes at a frequency of 0.0000203, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant was reported in multiple AT patients (Stankovic_1998, Skowronska_2012, Stewart_2001). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
OMIM RCV000206671 SCV000023313 pathogenic Ataxia-telangiectasia syndrome 1995-06-23 no assertion criteria provided literature only
OMIM RCV000003163 SCV000023321 pathogenic T-cell prolymphocytic leukemia 2002-09-01 no assertion criteria provided literature only
GeneReviews RCV000206671 SCV000328309 pathogenic Ataxia-telangiectasia syndrome 2016-10-27 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000417362 SCV000503545 uncertain significance Neoplasm of the breast 2016-08-01 no assertion criteria provided research Found in a male patient having exome sequencing for an unrelated indication. No known personal or family history of breast cancer.

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