ClinVar Genomic variation as it relates to human health

The best available variant frequency is uninformative because it is below the disease allele frequency. Found in at least one symptomatic patient. Predicted to negatively affect a known splice site. Occurs in three or more cases with a recessive pathogenic variant in the same gene. Damaging to protein function(s) relevant to disease mechanism.

DNA sequence analysis of the ATM gene demonstrated a sequence change close to the splice donor site of intron 57, c.8418+5_8418+8del. This sequencing change has been described in the gnomAD database with a low population frequency of 0.0007% (dbSNP rs1060499575). This sequence change has been previously reported in the compound heterozygous state in individuals with ataxia-telangiectasia (PMIDs: 30549301, 9872980, 10817650, 12552559, 28008555). It has also been reported in breast and prostate cancer patients (PMIDs: 26681312, 27433846). Functional study shows the c.8418+5_8418+8del variant causes a skipping of exon 57, and results in a short mRNA transcript with 150-base pair deletion (PMID: 8808599). Collectively these evidences indicate that, the c.8418+5_8418+8del sequence is pathogenic.

This c.8418+5_8418+8delGTGA variant in the ATM gene was experimentally demonstrated to cause exon skipping and result in a shortened mRNA transcript (PMID: 8808599). This variant has been reported in several individuals affected with ataxia-telangiectasia (MIM # 208900, PMID: 9872980, 10817650, 12552559) and in a patient affected with prostate cancer (PMID: 27433846). This variant has an extremely low frequency in large databases of genetic variation in the general population. Therefore, this c.8418+5_8418+8delGTGA variant in the ATM gene is classified as pathogenic.

Variant summary: ATM c.8418+5_8418+8delGTGA alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 5 splicing donor site. One predict the variant weakens a 5' donor site. Experimental studies have shown the variant to result in exon skipping (Wright_1996). The variant allele was found at a frequency of 4e-06 in 251020 control chromosomes. c.8418+5_8418+8delGTGA has been reported in the literature in multiple individuals affected with Ataxia-Telangiectasia in the compound heterozygous state (Buzin_2003, Hacia_1998, Li_2000, Pritzlaff_2017) as well as breast and prostate cancers in the heterozygous state (Pritchard_2016, Susswein_2016). Eight 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.

This variant deletes 4 nucleotides at the +5 to +8 position of intron 57 of the ATM gene. Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. RNA studies have shown that this variant causes the skipping of exon 57 (PMID: 8845835, 31843900), resulting in an in-frame deletion of 50 amino acids within the kinase domain of the ATM protein. Although protein functional studies have not been reported, this variant is expected to disrupt the kinase activity of the ATM protein. This variant (also known as c.8418+1_8418+4del, IVS59+1del4, IVS59+5_IVS59+8del and 8269del150 in the literature) has been reported in individuals affected with breast cancer (PMID: 16832357, 19781682, 26681312, 28008555) and prostate cancer (PMID: 27433846). This variant has also been reported in the compound heterozygous state in individuals affected with ataxia telangiectasia (PMID: 8808599, 8845835, 9463314, 9872980, 10817650, 12552559, 28008555). This variant has been identified in 2/282394 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.

The frequency of this variant in the general population, 0.000016 (2/128848 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMID: 32885271 (2021), 26681312 (2015), 19781682 (2009)), prostate cancer (PMID: 33436325 (2021), 32853339 (2021), 32338768 (2020)), and ataxia-telangiectasia (PMID: 9463314 (1998), 9872980 (1998), 30549301 (2019), 28008555 (2017)). This variant has also been shown to result in exon 59 skipping (PMID: 8808599 (1996)). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper ATM mRNA splicing. Based on the available information, this variant is classified as pathogenic.

This sequence change falls in intron 57 of the ATM gene. It does not directly change the encoded amino acid sequence of the ATM protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs769139997, gnomAD 0.002%). This variant has been observed in individuals with ATM-related conditions (PMID: 9872980, 10817650, 12552559, 26681312, 27433846). This variant is also known as c.8269delta150, 8418+1delGTGA, IVS59+1del4, and IVS59+5_IVS59+8delGTGA. ClinVar contains an entry for this variant (Variation ID: 181866). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 57 (also known as exon 59), but is expected to preserve the integrity of the reading-frame (PMID: 8808599; Invitae). For these reasons, this variant has been classified as Pathogenic.

The c.8418+5_8418+8delGTGA intronic pathogenic mutation (also known as c.8418+1_8418+4delGTGA) is located 5 nucleotides after coding exon 56 of the ATM gene. This mutation results from a deletion of 4 nucleotides at positions c.8418+5 to c.8418+8 which affects the splice donor site and was reported to result in the deletion of coding exon 56 (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59(4):839-46). RNA studies have shown skipping of coding exon 56 in samples with this alteration (Ambry internal data). This mutation has been reported as compound heterozygous in numerous patients with ataxia-telangiectasia (AT) (Wright J et al. Am. J. Hum. Genet. 1996 Oct;59(4):839-46; Stankovic T et al. Am. J. Hum. Genet. 1998 Feb;62(2):334-45; Li A and Swift M. Am. J. Med. Genet. 2000 May;92(3):170-7; Buzin CH et al. Hum. Mutat. 2003 Feb;21(2):123-31). This mutation has also been reported in individuals with male breast cancer (Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586), metastatic prostate cancer (Pritchard CC et al. N. Engl. J. Med. 2016 Aug;375:443-53), and breast cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). Based on available evidence, this alteration is interpreted as a disease-causing mutation.

Non-canonical splice site variant demonstrated to result in an in-frame deletion of a critical region (PMID: 31843900, 8808599); Observed in the heterozygous state in individuals with prostate, breast, or pancreatic cancer (PMID: 27433846, 32338768, 32853339, 33436325, 35047863); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9872980, 31447099, 30549301, 9463314, 10817650, 28008555, 12552566, 12552559, 26681312, 8808599, 23532176, 31843900, 33436325, 32338768, 32885271, 32866655, 32853339, 35047863, 29922827, 35078243, 27433846, 8845835)

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with ataxia-telangiectasia (MIM#208900), and cancer susceptibility (MIM#114480) (OMIM). Missense variants have been shown to interfere with endogenous ATM protein activity (PMID: 20301790, PMID: 19431188). (I) 0108 - This gene is associated with both recessive and dominant disease. Biallelic variants in this gene result in ataxia-telangiectasia, whereas heterozygous individuals have a greater susceptilbity to different forms of cancer (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. Variable age of onset and rate of disease progression have been reported for affected individuals within the same family (PMID: 20301790, PMID: 27884168). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown by RT-PCR to cause exon 57 skipping resulting in the inframe loss of 50 amino acids (p.(Val2757_Met2806del)) (PMID: 8845835, PMID: 31843900). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a condition (3 heterozygotes, 0 homozygotes). (SP) 0601 - Variant results in the partial loss of the well-established PI3K/PI4K domain, including multiple ATP binding sites (NCBI, UniProt). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported many times as pathogenic, and described in a compound heterozygous state in multiple individuals with ataxia-telangiectasia with or without cancer, and a heterozygous state in individuals with breast or prostate cancer (ClinVar, PMID: 27433846, PMID: 8845835, PMID: 31843900, PMID: 28008555). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8845835, 10817650, 12552559, 21792198].

The ATM c.8418+5_8418+8del variant was identified in 8 of 23168 proband chromosomes (frequency: 0.0003) from individuals or families with Ataxia-Telangiectasia (AT), breast cancer or prostate cancer (Buzin 2003, Li 2000, Pritchard 2016, Pritzaff 2016, Susswein 2015), including 1 homozygote affected with AT (Li 2000). The variant was also identified in dbSNP (ID: rs730881295) as "With Pathogenic allele", ClinVar (classified as pathogenic by Invitae, GeneDx, Ambry Genetics, and two other submitters). The variant was not identified in LOVD 3.0. The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.8418+5_8418+8del variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant is classified as pathogenic.

The ATM c.8418+5_8418+8delGTGA variant is predicted to result in an intronic deletion. This variant has been reported many times in the literature using different naming conventions, including: IVS57+5_IVS57+8delGTGA, IVS59+5_IVS59+8delGTGA, IVS59+1del4, 8418+1delGTGA, and 8269del150. It has been detected in the compound heterozygous state in several individuals with ataxia telangiectasia (Hacia et al. 1998. PubMed ID: 9872980; Li and Swift. 2000. PubMed ID: 10817650; Buzin et al. 2003. PubMed ID: 12552559; Pritzlaff et al. 2017. PubMed ID: 28008555) and in the heterozygous state in at least one individual with breast cancer (Susswein et al. 2016. PubMed ID: 26681312) and one individual with prostate cancer (Pritchard et al. 2016. PubMed ID: 27433846). This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD and is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181866/). Multiple in silico splicing prediction tools indicate that the variant dramatically weakens the nearby donor site (Alamut Visual v2.11), and RNA studies indicate that it causes exon skipping (Wright et al. 1996. PubMed ID: 8808599). Taken together, we interpret this variant to be pathogenic.