ClinVar Genomic variation as it relates to human health

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.

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.

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in the heterozygous state in individuals with ATM-related cancers (Yuille 2002, Buzin 2003, Skowronska 2012, Roberts 2012, Desmond 2015, Maxwell 2015, Schrader 2016, Decker 2017, Pritzlaff 2017); This variant is associated with the following publications: (PMID: 25525159, 10330348, 9463314, 25503501, 22585167, 26681312, 26556299, 28008555, 27159321, 26094658, 28779002, 30549301, 29922827, 28888541, 12091354, 8659541, 21933854, 24486587, 24763289, 12552559, 25032865, 18321536, 26270727, 21459046, 16953663, 28007021, 26786923, 27324988, 28716242, 28729543, 11756185, 9872980, 25326635, 30716324, 30620386, 30322717, 30113427, 31447099, 26896183, 32853339, 32885271, 31948886, 31285527)

NMD is expected as a result of this variant, and therefore the loss of a functional protein. Additionally, the variant was found in at least one symptomatic patient, and found in general population data at a frequency that is consistent with pathogenicity. Based on the available information, this variant is classified as pathogenic.

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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.

This sequence change creates a premature translational stop signal (p.Lys2756*) in the ATM gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). This variant is present in population databases (rs371638537, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (A-T), chronic lymphocytic leukemia, medulloblastoma, pancreatic cancer, breast cancer and prostate cancer (PMID: 8659541, 9463314, 10330348, 11756185, 12552559, 21933854, 22585167, 25503501, 26094658, 26681312, 28007021). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 135780). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.

This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.

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.

ATM: PVS1, PM2, PS3:Supporting

Based on the classification scheme VCGS_Germline_v1.3.5, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with ataxia-telangiectasia (MIM#208900) and susceptibility to breast cancer (MIM#114480). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants in this gene result in ataxia-telangiectasia; however, heterozygous carriers of specific pathogenic variants have an increased risk of breast cancer (PMID: 27595995). Germline variants in this gene may also contribute to increased risk of other cancers including gastric, colorectal, and pancreatic cancers, however the risk is not well-established at this stage (PMIDs: 22585167, 27978560, 26506520). (I) 0115 - Variants in this gene are known to have variable expressivity with regard to ataxia-telangiectasia. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMIDs: 20301790, 27884168). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v4: 71 heterozygotes, 1 homozygote). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic by clinical laboratories in ClinVar. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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.

The ATM c.8266A>T variant is predicted to result in premature protein termination (p.Lys2756*). This variant has been reported to be causative for ataxia telangiectasia, chronic lymphocytic leukemia, and breast and pancreatic cancer (Table 1, Telatar et al. 1996. PubMed ID: 8659541; Skowronska. et al. 2012. PubMed ID: 21933854; Roberts et al. 2012. PubMed ID: 22585167; Aloraifi et al. 2015. PubMed ID: 26094658). This variant is reported in 0.0039% of alleles in individuals of European (Non-Finnish) descent in gnomAD. It is interpreted as pathogenic by the vast majority of submitters in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/135780/). Nonsense variants in ATM are expected to be pathogenic. This variant is interpreted as pathogenic.