Submissions for variant NM_000051.4(ATM):c.3372C>G (p.Tyr1124Ter)

gnomAD frequency: 0.00001  dbSNP: rs587779833

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000211999	SCV000149085	pathogenic	not provided	2021-12-15	criteria provided, single submitter	clinical testing	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; Observed with a pathogenic variant on the opposite allele (in trans) and in apparent homozygous state in individuals with ataxia-telangiectasia in published literature (Li 2000, Minto 2019); Observed in individuals with breast cancer, prostate cancer, ovarian cancer, and medulloblastoma (Lilyquist 2017, Waszak 2018, Matejcic 2020, Palmer 2020); Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 10330348, 28888541, 32427313, 10817650, 32832836, 25525159, 26681312, 24113346, 28152038, 29753700, 30639167)
Ambry Genetics	RCV000115176	SCV000186133	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-13	criteria provided, single submitter	clinical testing	The p.Y1124* pathogenic mutation (also known as c.3372C>G), located in coding exon 22 of the ATM gene, results from a C to G substitution at nucleotide position 3372. This changes the amino acid from a tyrosine to a stop codon within coding exon 22. This alteration has been reported as both heterozygous and homozygous in individuals diagnosed with ataxia-telangiectasia (Teraoka SN et al. Am. J. Hum. Genet. 1999 Jun;64:1617-31; Li A and Swift M. Am. J. Med. Genet. 2000 May;92:170-7; Minto H et al. Clin Immunol, 2019 03;200:55-63). Additionally, this alteration was identified in individuals diagnosed with breast and prostate cancer (Susswein LR et al. Genet Med, 2016 08;18:823-32; Lovejoy LA et al. Genes (Basel), 2020 12;11:; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43). 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.
Counsyl	RCV000169463	SCV000220895	likely pathogenic	Ataxia-telangiectasia syndrome	2014-11-19	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV000169463	SCV000282930	pathogenic	Ataxia-telangiectasia syndrome	2023-12-29	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr1124*) 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 (rs587779833, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia and breast and lung cancer (PMID: 10330348, 10817650, 26681312). ClinVar contains an entry for this variant (Variation ID: 127371). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000515217	SCV000611164	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-12-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115176	SCV000911665	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 23 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 the homozygous and heterozygous state in individuals affected with ataxia telangiectasia (PMID: 10330348, 10817650). This variant has also been reported in an individual affected with breast and lung cancer (PMID: 26681312). This variant has been identified in 1/250920 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	RCV000169463	SCV000916541	pathogenic	Ataxia-telangiectasia syndrome	2017-10-31	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.3372C>G (p.Tyr1124X) 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. This variant was found in 1/245674 control chromosomes (gnomAD) at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). Multiple publications have cited the variant in affected individuals diagnosed with breast cancer or Ataxia-Telangiectasia. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Baylor Genetics	RCV003467025	SCV004212016	pathogenic	Familial cancer of breast	2024-03-18	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492455	SCV004240558	pathogenic	Breast and/or ovarian cancer	2022-10-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467025	SCV004933071	pathogenic	Familial cancer of breast	2024-01-22	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Natera, Inc.	RCV000169463	SCV002080317	pathogenic	Ataxia-telangiectasia syndrome	2020-07-30	no assertion criteria provided	clinical testing