Submissions for variant NM_000051.4(ATM):c.3850del (p.Thr1284fs)

dbSNP: rs876660865

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213614	SCV000278636	pathogenic	Hereditary cancer-predisposing syndrome	2021-05-31	criteria provided, single submitter	clinical testing	The c.3850delA pathogenic mutation, located in coding exon 25 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 3850, causing a translational frameshift with a predicted alternate stop codon (p.T1284Qfs*9). This mutation (designated as 3849delA) has been identified in an individual with pancreatic cancer and detected homozygous in an individual with ataxia-telangiectasia (Lovecek M et al. Cancer Manag Res, 2019 Jan;11:599-609; Sandoval N et al. Hum. Mol. Genet. 1999 Jan; 8(1):69-79). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000472137	SCV000546898	pathogenic	Ataxia-telangiectasia syndrome	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr1284Glnfs*9) 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 ataxia-telangiectasia and/or breast cancer (PMID: 9887333, 21833744, 26822949). ClinVar contains an entry for this variant (Variation ID: 234124). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000485880	SCV000568320	pathogenic	not provided	2020-09-02	criteria provided, single submitter	clinical testing	Frameshift 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 in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 9887333, 28492532, 21833744, 26822949, 29445900)
Counsyl	RCV000472137	SCV000678110	pathogenic	Ataxia-telangiectasia syndrome	2017-05-23	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000213614	SCV001357926	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-28	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 26 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 reported in the homozygous or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia-telangiectasia (PMID: 9887333, 21833744). This variant has also been reported in individuals affected with breast and pancreatic cancer (PMID: 26822949, 29445900). 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.
Myriad Genetics, Inc.	RCV004020698	SCV004932091	pathogenic	Familial cancer of breast	2024-01-23	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
CZECANCA consortium	RCV001270927	SCV001451731	pathogenic	Breast and/or ovarian cancer	2019-06-11	no assertion criteria provided	case-control
Natera, Inc.	RCV000472137	SCV001458197	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004547562	SCV004776524	pathogenic	ATM-related disorder	2024-02-14	no assertion criteria provided	clinical testing	The ATM c.3850delA variant is predicted to result in a frameshift and premature protein termination (p.Thr1284Glnfs*9). This variant was reported in individual(s) with ataxia-telangiectasia and/or breast cancer (examples: Table 2, Soukupova J et al 2011. PubMed ID: 21833744; Table 1, Lhota F et al 2016. PubMed ID: 26822949). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/234124/). Frameshift variants in ATM are considered pathogenic. In summary, this variant is interpreted as pathogenic.