ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.2502dup (p.Val835fs) (rs587779822)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235098 SCV000149065 pathogenic not provided 2018-10-01 criteria provided, single submitter clinical testing This duplication of one nucleotide in ATM is denoted c.2502dupA at the cDNA level and p.Val835SerfsX7 (V835SfsX7) at the protein level. The normal sequence, with the base that is duplicated in brackets, is GAGA[dupA]GTAG. The duplication causes a frameshift which changes a Valine to a Serine at codon 835, and creates a premature stop codon at position 7 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.2502dupA, also reported as ATM 2502insA, has been observed in both the homozygous and compound heterozygous state in individuals with Ataxia-telengiectasia (Telatar 1998, Sandoval 1999, Chessa 2009). We consider this variant to be pathogenic.
Ambry Genetics RCV000115156 SCV000187199 pathogenic Hereditary cancer-predisposing syndrome 2017-11-24 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Counsyl RCV000410349 SCV000486972 pathogenic Ataxia-telangiectasia syndrome 2016-09-16 criteria provided, single submitter clinical testing
Color RCV000115156 SCV000682060 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Invitae RCV000410349 SCV000748965 pathogenic Ataxia-telangiectasia syndrome 2019-11-26 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Val835Serfs*7) in the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families with ataxia-telangiectasia (PMID: 9443866, 19691550, 15843990). It has also been reported in individuals with breast cancer and melanoma (PMID: 26681312, 26023681). This variant is also known as 2502insA, c.2502_2503insA p.(Val835fs), and 2503_2504insA in the literature. ClinVar contains an entry for this variant (Variation ID: 127351). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000410349 SCV001361521 pathogenic Ataxia-telangiectasia syndrome 2019-01-14 criteria provided, single submitter clinical testing Variant summary: ATM c.2502dupA (p.Val835SerfsX7) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. p.Gln1017X, p.His1082fsX14, p.Tyr1124X). The variant was absent in 246196 control chromosomes. c.2502dupA has been reported in the literature in individuals affected with Ataxia-Telangiectasia and breast cancer (Chessa_2009, Sandoval_1999, Susswein_2015, Telatar_1998). These data indicate that the variant is likely to be associated with disease. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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