Submissions for variant NM_000051.4(ATM):c.8549T>A (p.Leu2850Ter)

gnomAD frequency: 0.00001  dbSNP: rs876658716

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215215	SCV000274337	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-23	criteria provided, single submitter	clinical testing	The p.L2850* pathogenic mutation (also known as c.8549T>A), located in coding exon 57 of the ATM gene, results from a T to A substitution at nucleotide position 8549. This changes the amino acid from a leucine to a stop codon within coding exon 57. 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.
GeneDx	RCV000519674	SCV000617954	pathogenic	not provided	2020-03-05	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; Not observed at a significant frequency in large population cohorts (Lek 2016); Observed in an individual with colon polyps (Rosenthal 2018); This variant is associated with the following publications: (PMID: 30267214)
Invitae	RCV000526852	SCV000622827	pathogenic	Ataxia-telangiectasia syndrome	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu2850*) 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 (no rsID available, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with colorectal cancer and adenomatous polyps (PMID: 30267214). ClinVar contains an entry for this variant (Variation ID: 230697). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000215215	SCV000682495	pathogenic	Hereditary cancer-predisposing syndrome	2023-10-10	criteria provided, single submitter	clinical testing	This variant changes 1 nucleotide in exon 58 of the ATM gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. To our knowledge, this variant has not been reported in individuals affected with ATM-related disorders in the literature. This variant has been identified in 1/251136 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	RCV000526852	SCV000916549	likely pathogenic	Ataxia-telangiectasia syndrome	2018-02-09	criteria provided, single submitter	clinical testing	Variant summary: ATM c.8549T>A (p.Leu2850X) 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. A truncation downstream of this position, c.8977C>T (p.Arg2993X) have been classified as pathogenic by our laboratory. To our knowledge, no occurrence of c.8549T>A in individuals affected with Ataxia-Telangiectasia and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories via ClinVar (evaluation after 2014) classified the variant as "pathogenic." Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	RCV000526852	SCV001338763	pathogenic	Ataxia-telangiectasia syndrome		criteria provided, single submitter	clinical testing	In addition, the heterozygous nonsense variant c.8549T>A; p.Leu2850Ter was detected in exon 58 in the ATM gene, which was derived from the patient's father. The variant replaces the codon for the amino acid leucine (TTG) with a premature stop codon (TAG). In the population-related database gnomAD it is once recorded in heterozygous form among the European population (allele frequency: 0.0003982%), in the other population-related databases it is not listed. In the phenotype-related database HGMD it is once identified as possibly pathogenic, in ClinVar it is assessed four times as pathogenic and once as likely pathogenic, in LOVD it is not listed. The ACMG classification for this variant is: pathogenic (Class 5: PVS1, PM2, PM3, PP5).
CeGaT Center for Human Genetics Tuebingen	RCV000519674	SCV001371328	pathogenic	not provided	2022-12-01	criteria provided, single submitter	clinical testing	ATM: PVS1, PM2
Baylor Genetics	RCV003469011	SCV004212096	pathogenic	Familial cancer of breast	2023-02-08	criteria provided, single submitter	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000526852	SCV004099375	pathogenic	Ataxia-telangiectasia syndrome	2023-10-30	no assertion criteria provided	clinical testing