Submissions for variant NM_000051.4(ATM):c.8371_8374del (p.Tyr2791fs)

dbSNP: rs1064793046

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000481743	SCV000564669	likely pathogenic	not provided	2017-09-18	criteria provided, single submitter	clinical testing	This deletion of four nucleotides in ATM is denoted c.8371_8374delTACA at the cDNA level and p.Tyr2791GlyfsX14 (Y2791GfsX14) at the protein level. The normal sequence, with the bases that are deleted in brackets, is AAGA[delTACA]GGCC. The deletion causes a frameshift which changes a Tyrosine to a Glycine at codon 2791, and creates a premature stop codon at position 14 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. ATM c.8371_8374delTACA, also published as ATM c.8369GATAC>G using alternate nomenclature, has been observed in one individual with breast cancer and a strong family history of gastric cancer as well as in one individual with a Lynch syndrome-associated cancer and/or polyps (Hansford 2015, Yurgelun 2015). Based on the currently available information, we consider this deletion to be a likely pathogenic variant.
Color Diagnostics, LLC DBA Color Health	RCV000581187	SCV000687825	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	clinical testing	This variant deletes 4 nucleotides in exon 57 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 observed in individuals affected with breast cancer (PMID: 26182300) and pancreatic cancer (Color Health internal data). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000696221	SCV000824773	pathogenic	Ataxia-telangiectasia syndrome	2023-09-06	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr2791Glyfs*14) 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 premature translational stop signal has been observed in individual(s) with breast cancer and suspected Lynch syndrome (PMID: 25980754, 26182300). This variant is also known as c.8369GATAC>G. ClinVar contains an entry for this variant (Variation ID: 418047). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000581187	SCV001178753	pathogenic	Hereditary cancer-predisposing syndrome	2024-03-21	criteria provided, single submitter	clinical testing	The c.8371_8374delTACA pathogenic mutation, located in coding exon 56 of the ATM gene, results from a deletion of 4 nucleotides at nucleotide positions 8371 to 8374, causing a translational frameshift with a predicted alternate stop codon (p.Y2791Gfs*14). In a study of patients with a personal and/or family histories that were concerning for Hereditary Diffuse Gastric Cancer syndrome, this variant was been observed in a patient with breast cancer at age 59, who also had a family history of pancreatic and other cancers (Hansford S et al. JAMA Oncol, 2015 Apr;1:23-32). This variant was also reported in a patient diagnosed with pancreatic cancer under the age of fifty (Hutchings D et al. Mod Pathol, 2019 12;32:1806-1813). 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.
Baylor Genetics	RCV003470522	SCV004211974	pathogenic	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003470522	SCV004931117	pathogenic	Familial cancer of breast	2024-02-01	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.