ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.3576G>A (p.Lys1192=) (rs587776551)

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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 RCV000165646 SCV000216383 pathogenic Hereditary cancer-predisposing syndrome 2019-10-28 criteria provided, single submitter clinical testing Functionally-validated splicing mutation ;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Last nucleotide of exon
GeneDx RCV000236731 SCV000293312 pathogenic not provided 2017-10-09 criteria provided, single submitter clinical testing This variant is denoted ATM c.3576G>A at the DNA level and is located in the last nucleotide of exon 24, previously reported in the literature as exon 26. ATM c.3576G>A is silent at the coding level, preserving a Lysine at codon 1192. While the literature agrees that this variant disrupts a natural splice donor site, leading to abnormal splicing, there are some inconsistencies between reports. For example, this variant has been variably reported to result in transcripts with a deletion of exon 24, a deletion of exons 24-25, and/or a residual amount of normal transcripts; similarly, ATM protein has been reported as absent and as only moderately reduced (Sandoval 1999, Teraoka 1999, Demuth 2011, Jacquemin 2012, Verhagen 2012). However this variant has been consistently reported to demonstrate very low to absent ATM kinase activity (Demuth 2011, Jacquemin 2012, Verhagen 2012).
Counsyl RCV000003174 SCV000485198 pathogenic Ataxia-telangiectasia syndrome 2016-03-08 criteria provided, single submitter clinical testing
Invitae RCV000003174 SCV000546861 pathogenic Ataxia-telangiectasia syndrome 2019-11-21 criteria provided, single submitter clinical testing This sequence change affects codon 1192 of the ATM mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the ATM protein. It also falls at the last nucleotide of exon 24 of the ATM coding sequence. This variant is present in population databases (rs587776551, ExAC 0.003%). This variant has been reported in several individuals and families affected with ataxia-telangiectasia (PMID: 22071889, 19691550, 17124347, 9887333, 8845835) as well as in an individual affected with early-onset breast and thyroid cancer (PMID: 27599564). This variant is also known as 3403del174 in the literature. ClinVar contains an entry for this variant (Variation ID: 3035). Experimental studies have shown that this sequence change results in aberrant splicing of the ATM mRNA, reduced ATM abundance, and defective ATM protein function (PMID: 22071889, 9887333). For these reasons, this variant has been classified as Pathogenic.
Color RCV000165646 SCV000682142 pathogenic Hereditary cancer-predisposing syndrome 2019-09-25 criteria provided, single submitter clinical testing
Mendelics RCV000003174 SCV000838524 pathogenic Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000003174 SCV000916595 pathogenic Ataxia-telangiectasia syndrome 2018-09-24 criteria provided, single submitter clinical testing Variant summary: ATM c.3576G>A (p.Lys1192Lys) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. Two predict the variant weakens a 5' donor site. An experimental study, Demuth_2011, supports these predictions by finding that this variant is associated with an in-frame exclusion of exon 26 from the mRNA. The variant allele was found at a frequency of 1.6e-05 in 246056 control chromosomes (gnomAD). The variant, c.3576G>A, has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia (Chessa_2009, Demuth_2011). These data indicate that the variant is very likely to be associated with disease. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000236731 SCV001249802 pathogenic not provided 2019-05-01 criteria provided, single submitter clinical testing
OMIM RCV000003174 SCV000023332 pathogenic Ataxia-telangiectasia syndrome 1999-01-01 no assertion criteria provided literature only

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