ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.8266A>T (p.Lys2756Ter) (rs371638537)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122886 SCV000166144 pathogenic Ataxia-telangiectasia syndrome 2020-10-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal at codon 2756 (p.Lys2756*) of the ATM gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs371638537, ExAC 0.002%). This variant has been observed in individuals affected with ataxia-telangiectasia (A-T) (PMID: 10330348, 12552559, 8659541, 9463314), chronic lymphocytic leukemia (PMID: 11756185, 21933854), medulloblastoma (PMID: 28007021), pancreatic cancer (PMID: 22585167), breast cancer and prostate cancer (PMID: 26094658, 25503501, 26681312). ClinVar contains an entry for this variant (Variation ID: 135780). Experimental studies have shown that reprogrammed A-T cells carrying this variant exhibit partially disrupted ATM protein function, such as defective repair of DNA double-strand breaks and repressed phosphorylation of ATM substrates (PMID: 25032865). Loss-of-function variants in ATM are known to be pathogenic (PMID: 25614872, 23807571). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000128904 SCV000172765 pathogenic Hereditary cancer-predisposing syndrome 2019-05-07 criteria provided, single submitter clinical testing The p.K2756* pathogenic mutation (also known as c.8266A>T), located in coding exon 55 of the ATM gene, results from an A to T substitution at nucleotide position 8266. This changes the amino acid from a lysine to a stop codon within coding exon 55. This mutation has been reported in multiple individuals diagnosed with ataxia-telangiectasia (A-T) (Telatar M et al. Am. J. Hum. Genet. 1996 Jul;59:40-4; Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Buzin CH et al. Hum. Mutat. 2003 Feb;21:123-31). This alteration has also been detected in individuals with personal and/or family histories of breast cancer (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8; Aloraifi F et al. FEBS J. 2015 Sep;282:3424-37; Desmond A et al. JAMA Oncol. 2015 Oct;1:943-51). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation.
GeneDx RCV000212082 SCV000209653 pathogenic not provided 2018-12-24 criteria provided, single submitter clinical testing This pathogenic variant is denoted ATM c.8266A>T at the cDNA level and p.Lys2756Ter (K2756X) at the protein level. The substitution creates a nonsense variant, changing a Lysine to a premature stop codon (AAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in association with ataxia-telangiectasia, chronic lymphocytic leukemia, colorectal cancer, and familial pancreatic cancer (Telatar 1996, Stankovic 1998, Teraoka 1999, Yuille 2002, Buzin 2003, Kato 2006, Du 2008, Skowronska 2012, Roberts 2012, Schrader 2015, Vanderver 2016). ATM Lys2756Ter has also been observed in individuals with familial breast cancer and prostate cancer (Maxwell 2014, Desmond 2015, Pritzlaff 2017). We therefore consider this variant to be pathogenic.
Counsyl RCV000122886 SCV000220141 likely pathogenic Ataxia-telangiectasia syndrome 2014-03-04 criteria provided, single submitter literature only
Color Health, Inc RCV000128904 SCV000682472 pathogenic Hereditary cancer-predisposing syndrome 2021-01-26 criteria provided, single submitter clinical testing This variant changes 1 nucleotide in exon 56 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with ataxia telangiectasia (PMID: 8659541, 9463314, 10330348, 12552559, 21665257). This variant has also been reported in individuals affected with breast cancer (PMID: 20305132, 25503501, 26094658, 26534844. 26681312, 28008555) and pancreatic cancer (PMID: 22585167). This variant has been identified in 5/282078 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATM function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000122886 SCV000694375 pathogenic Ataxia-telangiectasia syndrome 2016-08-11 criteria provided, single submitter clinical testing Variant summary: The ATM c.8266A>T (p.Lys2756X) variant results in a premature termination codon, predicted to cause a truncated or absent ATM 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 (e.g.c.8264_8268delATAAG/p.Tyr2755fsX12). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/118602 control chromosomes at a frequency of 0.0000084, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0039528). This variant has been reported in multiple patients with AT and different types of cancers. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics RCV000122886 SCV000807217 pathogenic Ataxia-telangiectasia syndrome 2017-09-01 criteria provided, single submitter clinical testing This mutation has been previously reported as disease-causing and was found once in our laboratory in trans with a deleterious intronic mutation in a 7-month-old female with immune deficiency, hearing loss, and skin lesion.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356913 SCV001552200 pathogenic Familial ovarian cancer no assertion criteria provided clinical testing The ATM p.Lys2756* variant was identified in 9 of 23570 proband chromosomes (frequency: 0.0004) from individuals or families with breast or pancreatic cancer or ataxia-telangiectasia and was not identified in 582 control chromosomes from healthy individuals (Aloraifi 2015, Susswein 2015, Maxwell 2014, Desmond 2015, Buzin 2003, Roberts 2012, Stankovic 1998, Telatar 1996). In one of these studies, the variant was found to segregate with disease in the affected pancreatic kindred and tumour analysis showed loss of wildtype allele (Roberts 2012).The variant was also identified in dbSNP (ID: rs371638537 as “With Pathogenic, Uncertain significance allele”), ClinVar (classified pathogenic by Invitae, Ambry Genetics, GeneDx, Color Genomics and Integrated Genetics/Laboratory Corporation of America and as likely pathogenic by Counsyl), Cosmic (in a lymphoid neoplasm/CLL), and LOVD 3.0 (1x). The variant was not identified in GeneInsight-COGR or MutDB databases. The variant was identified in control databases in 5 of 276440 chromosomes at a frequency of 0.00002 (Genome Aggregation Database Feb 27, 2017), specifically in the European Non-Finnish population in 5 of 126164 chromosomes (freq: 0.00004) and was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. The variant was found to co-occur with several pathogenic variants: CHEK2 c.1100delC p.Thr367Metfs*15; CHEK2 c.1263delT p.Ser422Valfs*15; and CHEK2 c.444+1G>A in 3 breast cancer patients and ATM c.2250G>A, c.2125del126; and ATM c.1058_1059delGT in 2 ataxia-telangiectasia patients (Teraoka 1999, Skowronska 2012, Susswein 2015, Maxwell 2014). The ATM c.8266A>T variant also occurs in the last three bases of exon 56. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. Further, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a difference in splicing. The p.Lys2756* variant is predicted to create a premature stop codon at position 2756, which is then predicted to lead to a truncated or absent protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in hereditary breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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