Submissions for variant NM_000051.4(ATM):c.5290del (p.Leu1764fs)

gnomAD frequency: 0.00001  dbSNP: rs587779846

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV003467027	SCV004565378	pathogenic	Familial cancer of breast	2024-01-25	reviewed by expert panel	curation	The c.5290del (p.Leu1764TyrfsTer12) variant in ATM is a frameshift variant predicted to cause a premature stop codon in a biologically-relevant-exon leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism. This alteration results in a termination codon upstream of the most C-terminus pathogenic alteration (ATM p.Arg3047*), as classified by the HBOP VCEP, and is expected to be more deleterious. This variant has been detected in at least four individuals with Ataxia-Telangiectasia (PMIDs: 22649200, 10425038, 12552559, 18634022, 15928302, 10330348, 18634022, 26896183). The highest population minor allele frequency in gnomAD v2.1.1 is 0.00001763 in the non-Finnish European population (PM2_Supporting, BS1, and BA1 are not met). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant hereditary breast cancer and autosomal recessive Ataxia-Telangiectasia based on the ACMG/AMP criteria applied, as specified by the HBOP VCEP. (PVS1, PM3_Strong, PM5_Supporting)
GeneDx	RCV000235105	SCV000149119	pathogenic	not provided	2022-07-27	criteria provided, single submitter	clinical testing	Frameshift 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 individuals with breast and other cancers (Renwick et al., 2006; Lu et al., 2015; Maxwell et al., 2016; Decker et al., 2017); Observed in individuals with ataxia telangiectasia (Castellvi-Bel et al.,1999; Teraoka et al., 1999; Sun et al., 2002; Buzin et al., 2003); This variant is associated with the following publications: (PMID: 10330348, 30197789, 29625052, 12552559, 9887333, 12072877, 16832357, 10425038, 26681312, 27153395, 24763289, 18634022, 20346647, 26689913, 28152038, 28843361, 28779002, 26896183)
Ambry Genetics	RCV000115210	SCV000183971	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-03	criteria provided, single submitter	clinical testing	The c.5290delC pathogenic mutation, located in coding exon 34 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 5290, causing a translational frameshift with a predicted alternate stop codon (p.L1764Yfs*12). This pathogenic mutation has been detected in an ataxia-telangiectasia (A-T) cell line and in individuals with A-T (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Sun X et al. J. Pediatr. 2002 Jun;140:724-31; Thompson D et al. J. Natl. Cancer Inst. 2005 Jun;97:813-22; Carney EF et al. J Immunol, 2012 Jul;189:261-8). This mutation has also been reported in multiple breast and/or ovarian cancer families (Renwick A et al. Nat Genet, 2006 Aug;38:873-5; Maxwell KN et al. Am J Hum Genet, 2016 May;98:801-817; Decker B et al. J Med Genet, 2017 11;54:732-741). In one study, this variant was reported in 2/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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.
Counsyl	RCV000169483	SCV000220935	likely pathogenic	Ataxia-telangiectasia syndrome	2014-12-04	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169483	SCV000253739	pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1764Tyrfs*12) 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 frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast cancer (PMID: 10330348, 10425038, 12552559, 16832357, 22649200, 26681312). ClinVar contains an entry for this variant (Variation ID: 127405). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000115210	SCV000682261	pathogenic	Hereditary cancer-predisposing syndrome	2023-02-17	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 35 of the ATM gene, creating a frameshift and 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: 10330348, 10425038, 12552559, 18634022, 22649200). This variant has also been reported in individuals affected with breast cancer (PMID: 16832357, 19781682, 26681312, 28779002) and lung cancer (PMID: 28843361). In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and 1/53461 unaffected controls (PMID: 33471991). This variant has been identified in 2/251112 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000169483	SCV000916586	pathogenic	Ataxia-telangiectasia syndrome	2018-08-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.5290delC (p.Leu1764TyrfsX12) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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 (eg. c.5712dupA/p.Ser1905fsX25, c.5908C>T/p.Gln1970X). The variant allele was found at a frequency of 8.3e-06 in 121178 control chromosomes. c.5290delC has been reported in the literature in individuals affected with Ataxia-Telangiectasia (Castellvi-Bev_1999, Sun_2002, Thompson_2005). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. Three 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.
Sema4, Sema4	RCV000115210	SCV002528397	pathogenic	Hereditary cancer-predisposing syndrome	2021-11-15	criteria provided, single submitter	curation
Athena Diagnostics	RCV000235105	SCV002771604	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149794	SCV003837845	pathogenic	Breast and/or ovarian cancer	2022-06-03	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549557	SCV004120852	pathogenic	ATM-related disorder	2022-08-18	criteria provided, single submitter	clinical testing	The ATM c.5290delC variant is predicted to result in a frameshift and premature protein termination (p.Leu1764Tyrfs*12). This variant has been reported in the heterozygous state in several individuals with breast cancer (See for example, Susswein et al. 2015. PubMed ID: 26681312, Supp. Table S1; Decker et al. 2017. PubMed ID: 28779002, Supp. Table S5) and at least one individual with lung adenocarcinoma (Lu et al. 2015. PubMed ID: 26689913, Supp. Table S2). This variant has also been reported in the biallelic state in individuals with ataxia telangiectasia (Sun et al. 2002. PubMed ID: 12072877). This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/11-108172486-TC-T). Frameshift variants in ATM are expected to be pathogenic. This variant is classified as likely pathogenic and pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/127405/). This variant is interpreted as pathogenic.
Baylor Genetics	RCV003467027	SCV004212065	pathogenic	Familial cancer of breast	2024-03-28	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000235105	SCV004221157	pathogenic	not provided	2022-09-08	criteria provided, single submitter	clinical testing	This frameshift variant alters the translational reading frame of the ATM mRNA and causes the premature termination of ATM protein synthesis. The frequency of this variant in the general population, 0.000018 (2/113458 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. In the published literature, the variant has been reported in individuals with ataxia-telangiectasia (PMIDs: 10330348 (1999), 10425038 (1999), 12552559 (2003), 15928302 (2005), 22649200 (2012), and 26896183 (2016)) and breast cancer (PMIDs: 16832357 (2006), 26681312 (2015), and 28779002 (2017)). Based on the available information, this variant is classified as pathogenic.
Myriad Genetics, Inc.	RCV003467027	SCV004932930	pathogenic	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000169483	SCV001452314	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing