ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.6976-10_6989del (rs587779859)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115237 SCV000149146 pathogenic Hereditary cancer-predisposing syndrome 2014-06-20 criteria provided, single submitter clinical testing This variant is denoted ATM c.6976-10_6989del24 and consists of a deletion of 24 nucleotides at the -10 position of intron 47. The surrounding sequence and deleted bases are cctt{tcttatacagAACAATCCCAGCCT}AAAAC, where the lower case letters are intronic bases and upper case exonic. The deletion spans the intron-exon boundary, resulting in loss of the canonical splice acceptor site. It is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Although the mutation has not, to our knowledge, been published in the literature, it is considered pathogenic. One mutation in the ATM gene has been estimated to increase the relative risk of female breast cancer about 2-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's partner is also heterozygous for an ATM mutation, the risk to have a child with A-T is 25% with each pregnancy. The variant is found in PANC-HEREDIC,BR-OV-HEREDIC panel(s).
Invitae RCV000456935 SCV000546948 likely pathogenic Ataxia-telangiectasia syndrome 2016-12-11 criteria provided, single submitter clinical testing This sequence change deletes 24 nucleotides at an intron-exon junction and affects an acceptor splice site in intron 48 of the ATM gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant has not been reported in the literature in individuals with a ATM-related disease. ClinVar contains an entry for this variant (Variation ID: 127432). In summary, donor and acceptor splice site variants are typically loss-of-function (PMID: 16199547), and loss-of-function variants in ATM are known to be pathogenic (PMID: 10817650, 19781682). However, without additional functional and/or genetic data, this variant has been classified as Likely Pathogenic.
Color Health, Inc RCV000115237 SCV001350510 likely pathogenic Hereditary cancer-predisposing syndrome 2019-08-13 criteria provided, single submitter clinical testing

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