ClinVar Genomic variation as it relates to human health

This variant changes 1 nucleotide in exon 39 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 trans with another ATM mutation in an individual affected with ataxia-telangiectasia (PMID: 18321536) and in individuals affected with breast cancer (Color Health, Inc.). This variant has not been identified 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.

For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 182000). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 18321536). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Lys1964*) 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).

The p.K1964* pathogenic mutation (also known as c.5890A>T), located in coding exon 38 of the ATM gene, results from an A to T substitution at nucleotide position 5890. This changes the amino acid from a lysine to a stop codon within coding exon 38. This alteration has been reported in a compound heterozygous state in an individual affected with ataxia-telangiectasia (Du L et al. Mutat. Res., 2008 Apr;640:139-44). This alteration has also been detected in 1/5054 African American breast cancer patients and 0/4993 unaffected African American controls (Palmer JR et al. J Natl Cancer Inst, 2020 12;112:1213-1221). In a study looking at cancer predisposition mutations in patients with cutaneous melanoma and a history of at least two additional non-cutaneous melanoma primary cancers, this alteration was identified in 1/1358 non-cancer control individuals and in 0/57 cases (Pritchard AL et al. PLoS One, 2018 Apr;13:e0194098). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.

Based on the classification scheme VCGS_Germline_v1.3.4, 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 (AT; 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 AT. 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) 0301 - Variant is absent from gnomAD (both v2 and v3). (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 classified as pathogenic or likely pathogenic by multiple clinical laboratories in ClinVar, and has been observed in an individual with breast cancer (PMID: 32427313). This variant has also been observed in an individual with AT who harboured a second ATM variant; however, it is not known if the variants are in trans (PMID: 18321536). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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); Identified in individuals with breast cancer (Palmer et al., 2020); Observed with a pathogenic ATM variant in a patient with ataxia-telangiectasia, but it is not known whether the variants occurred on the same (in cis) allele or on opposite (in trans) alleles (Du et al., 2008); This variant is associated with the following publications: (PMID: 25525159, 32427313, 18321536)

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