Submissions for variant NM_000051.4(ATM):c.6273del (p.Trp2091fs)

dbSNP: rs1565503137

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000768150	SCV000898529	pathogenic	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-11-23	criteria provided, single submitter	clinical testing	ATM NM_000051 exon 43 p.Trp2091Cysfs*5 (c.6273del): This variant has not been reported in the literature and is is not present in large control databases. Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant is a deletion of 1 nucleotide and creates a premature stop codon 5 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Huang 2013 PMID:23807571) . In summary, this variant is classified as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001280579	SCV001467786	likely pathogenic	Malignant tumor of breast	2020-12-15	criteria provided, single submitter	clinical testing	Variant summary: ATM c.6273delG (p.Trp2091CysfsX5) 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. The variant was absent in 251422 control chromosomes (gnomAD). To our knowledge, no occurrence of c.6273delG in individuals affected with Breast Cancer and no experimental evidence demonstrating its impact on protein function have been reported. One co-occurrence with another pathogenic variant has been internally reported (ATM c.7913G>A, p.Trp2638X). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Myriad Genetics, Inc.	RCV003453588	SCV004187079	pathogenic	Familial cancer of breast	2023-09-20	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Invitae	RCV003500587	SCV004249612	pathogenic	Ataxia-telangiectasia syndrome	2024-01-07	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Trp2091Cysfs*5) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ATM-related conditions. ClinVar contains an entry for this variant (Variation ID: 626061). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV004027212	SCV005018808	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-26	criteria provided, single submitter	clinical testing	The c.6273delG pathogenic mutation, located in coding exon 42 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 6273, causing a translational frameshift with a predicted alternate stop codon (p.W2091Cfs*5). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.