Submissions for variant NM_000051.4(ATM):c.1122_1123del (p.Glu376fs)

dbSNP: rs1591517571

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen	RCV002221598	SCV002499293	pathogenic	Familial cancer of breast	2022-04-14	reviewed by expert panel	curation	The ATM c.1122_1123del (p.Glu376IlefsTer2) variant has a GnomAD (v2.1.1) allele frequency of 0.0000% which is below the ATM PM2 threshold of 0.001% (PM2_Supporting). This variant is expected to produce an NMD-prone transcript due to a nonsense or frameshifting event (PVS1). In the absence of potential splicing rescue mechanisms in ATM, all PVS1-eligble truncating variants are expected to be pathogenic based on the existence of known pathogenic C-terminal truncations in the last exon (PM5_Supporting). This variant has been observed in a compound heterozygous state (presumed) in one individual with Ataxia-Telangiectasia (PMID: 24954719 PM3). In summary, this variant meets criteria to be classified as pathogenic based on the ACMG/AMP criteria applied as specified by the HBOP Variant Curation Expert Panel.
Ambry Genetics	RCV001009889	SCV001170014	pathogenic	Hereditary cancer-predisposing syndrome	2023-09-06	criteria provided, single submitter	clinical testing	The c.1122_1123delAA variant, located in coding exon 8 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 1122 to 1123, causing a translational frameshift with a predicted alternate stop codon (p.E376Ifs*2). This alteration (designated as c.1121_1122delAA) has also been reported in the compound heterozygous state in a patient affected with ataxia telangiectasia (Nakayama T et al. Brain Dev., 2015 Mar;37:362-5). 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030518	SCV001193466	likely pathogenic	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001385543	SCV001585432	pathogenic	Ataxia-telangiectasia syndrome	2023-09-03	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 818362). For these reasons, this variant has been classified as Pathogenic. This variant is also known as c.1121_1122delAA. This premature translational stop signal has been observed in individual(s) with breast cancer and ataxia telangiectasia (PMID: 24954719, 32566746). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu376Ilefs*2) 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).
Myriad Genetics, Inc.	RCV002221598	SCV004932396	pathogenic	Familial cancer of breast	2024-01-12	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Laboratory for Genotyping Development, RIKEN	RCV003160173	SCV002758388	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research