ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.7998dup (p.Met2667fs) (rs587779869)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115259 SCV000185259 pathogenic Hereditary cancer-predisposing syndrome 2013-11-26 criteria provided, single submitter clinical testing
Color RCV000115259 SCV000682448 pathogenic Hereditary cancer-predisposing syndrome 2016-07-20 criteria provided, single submitter clinical testing
Counsyl RCV000409494 SCV000485517 likely pathogenic Ataxia-telangiectasia syndrome 2015-12-28 criteria provided, single submitter clinical testing
GeneDx RCV000766525 SCV000149168 pathogenic not provided 2013-10-08 criteria provided, single submitter clinical testing This variant is denoted c.7998_7999insT (aka c.7998dupT) at the cDNA level and p.Met2667TyrfsX4 (M2667YfsX4) at the protein level. The surrounding sequence is TACT{insT}ATGG. The insertion causes a frameshift, changing a Methionine to a Tyrosine at codon 2667, and creating a premature stop codon at position 4 of the new reading frame. This mutation is predicted to cause loss of normal protein function through either protein truncation or nonsense mediated mRNA decay. Although this pathogenic variant has not been previously reported to our knowledge, its presence is consistent with an increased cancer risk. One mutation in the ATM gene has been estimated to increase the relative risk of female breast cancer 2.23-2.37 fold over the general population (Thompson 2005, Renwick 2006) resulting in a lifetime risk of approximately 25-30%. According to one study, breast cancer risk in women under age 50 who carry one ATM mutation is nearly 5 times the age-matched general population risk which translates to approximately a 10% risk (Thompson 2005). This study of 1160 ATM carriers also reported evidence of increased risk for colon cancer. In a recent study of 166 unrelated familial pancreatic cancer patients, 2.4% were identified as carriers of one ATM mutation, and in families with 3 or more cases of pancreatic cancer, 4.6% carried an ATM mutation (Roberts 2012). Ataxia-telangiectasia (A-T) is an autosomal recessive condition caused by two mutations (one affecting each allele) in the ATM gene. This multisystem disorder is characterized by progressive neurodegeneration, telangiectasias, immunodeficiency, and increased cancer risks. If an ATM mutation carrier'spartner is also heterozygous for an ATM mutation, the risk to have a child with A-T is 25% with each pregnancy.
Invitae RCV000409494 SCV000945368 pathogenic Ataxia-telangiectasia syndrome 2018-10-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Met2667Tyrfs*4) 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 an individual affected with breast and gastric cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 127453). Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). For these reasons, this variant has been classified as Pathogenic.

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