ClinVar Miner

Submissions for variant NM_001330368.2(C11orf65):c.641-26890_641-26886del (rs730881294)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159623 SCV000209609 pathogenic not provided 2018-06-01 criteria provided, single submitter clinical testing This deletion of five nucleotides in ATM is denoted c.8264_8268delATAAG at the cDNA level and p.Tyr2755CysfsX12 (Y2755CfsX12) at the protein level. The normal sequence using uppercase letters to denote exonic sequence and lowercase letters to denote intronic sequence, with the bases that are deleted in brackets, is ACTT[delATAAG]gtaa. The deletion causes a frameshift, which changes a Tyrosine to a Cysteine at codon 2755, and creates a premature stop codon at position 12 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. An additional possible mechanism of pathogenicity is that given this deletion's location at the exon/intron boundary, this variant may result in aberrant splicing and skipping of exon 56 (also reported as exon 58 using alternate exon numbering) (Laake 2000, Tavtigian 2009). Whether the effect of this variant is that of a frameshift or splicing defect, the resultant protein would be impaired. ATM c.8264_8268delATAAG has been observed in the compound heterozygous state in patients with Ataxia-telangiectasia (Stankovic 1998, Mitui 2003, Demuth 2011, Carranza 2017), and in the single heterozygous state in individuals with breast cancer (Tavtigian 2009, Gra?a 2011, Ellingson 2015, Decker 2017). Furthermore, functional studies showed that this variant was associated with no detectable kinase activity (Barone 2009). We consider this variant to be pathogenic.
Center for Individualized Medicine,Mayo Clinic RCV000190640 SCV000245683 pathogenic Ataxia-telangiectasia syndrome 2014-01-01 criteria provided, single submitter research
Center of Genomic medicine, Geneva,University Hospital of Geneva RCV000190640 SCV000268516 pathogenic Ataxia-telangiectasia syndrome 2016-09-12 criteria provided, single submitter clinical testing This heterozygous variant in the ATM gene (autosomal recessive transmission), inherited from the mother, was present in a female patient who also harbours a second variant in the same gene inherited by the father (compound heterozygosity).
Ambry Genetics RCV000221664 SCV000274579 pathogenic Hereditary cancer-predisposing syndrome 2018-07-26 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s)
Invitae RCV000190640 SCV000283075 pathogenic Ataxia-telangiectasia syndrome 2019-10-15 criteria provided, single submitter clinical testing This sequence change deletes 5 nucleotides from exon 56 of the ATM mRNA (c.8264_8268delATAAG), causing a frameshift at codon 2755. This creates a premature translational stop signal (p.Tyr2755Cysfs*12) and is expected to result in a disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic. This particular variant has been well described in the literature as a recurrent, causative mutation in individuals affected with ataxia-telangiectesia (PMID: 9463314, 12815592, 21965147, 10980530). This variant has also been reported in individuals affected with breast cancer (PMID: 21445571, 26296701, 26681312) and has been reported to incur a 2-fold risk for developing breast cancer (PMID: 20346647). ClinVar contains an entry for this variant (Variation ID: 181865). Experimental studies have reported that this variant causes aberrant splicing and results in an mRNA transcript lacking exon 56 (also reported as exon 58) (PMID: 15039971, 21792198). Additional publications have reported that although this variant produces a protein product that allows for ATM expression, this protein lacks the kinase activity required for normal function of the ATM protein (PMID: 19431188). For these reasons, this variant has been classified as Pathogenic.
Color RCV000221664 SCV000682470 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000190640 SCV000694374 pathogenic Ataxia-telangiectasia syndrome 2015-11-25 criteria provided, single submitter clinical testing Variant summary: The variant is a deletion of five nucleotides spanning over the border of exon and intron 56. 5/5 in silico tools via Alamut predict this deletion to result in loss of splice donor site along with mutation taster predicting disease causing outcome. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.00084% which does not exceed the maximal expected allele frequency of a disease causing ATM allele (0.4%). It was reported in AT patients in compound heterozygosity with potentially pathogenic ATM variants and was also observed in breast cancer patients in a heterozygous form indicating the variant to be pathogenic for both AT and breast cancer. Additionally, clinical diagnostic laboratories classify variant as Pathogenic via ClinVar (without evidence to independently evaluate). Considering all evidence, the variant is classified as pathogenic.
Counsyl RCV000190640 SCV000793072 pathogenic Ataxia-telangiectasia syndrome 2017-08-02 criteria provided, single submitter clinical testing
Mendelics RCV000190640 SCV000838611 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing

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