Submissions for variant NM_000051.4(ATM):c.43del (p.Gln14_Leu15insTer)

dbSNP: rs771887195

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000223089	SCV000277064	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-09	criteria provided, single submitter	clinical testing	The c.43delC pathogenic mutation, located in coding exon 1 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 43, causing a translational frameshift with a predicted alternate stop codon (p.L15*). This mutation has been identified in hereditary breast and/or ovarian cancer cohorts (Fonfria M et al. J Pers Med 2021 Jun;11(6); Cock-Rada M et al. Fam Cancer 2018 01;17(1):23-30). One case-control study detected this mutation in 0/3030 pancreatic cancer cases and 2/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). 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.
GeneDx	RCV000481023	SCV000564600	pathogenic	not provided	2019-11-05	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 individuals with ATM-related cancers (Cock-Rada 2017, Decker 2017); This variant is associated with the following publications: (PMID: 28528518, 28779002)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628079	SCV000748969	pathogenic	Ataxia-telangiectasia syndrome	2023-12-26	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu15*) 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 (rs771887195, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 28528518, 28779002). ClinVar contains an entry for this variant (Variation ID: 232822). RNA analysis performed to evaluate the impact of this premature translational stop signal on mRNA splicing indicates it does not significantly alter splicing (Invitae). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000223089	SCV001349317	pathogenic	Hereditary cancer-predisposing syndrome	2020-08-25	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 2 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 an individual affected with familial breast cancer (PMID: 28528518, 31658756). This variant has been identified in 1/251400 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.
Baylor Genetics	RCV003469059	SCV004210085	pathogenic	Familial cancer of breast	2023-08-04	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003469059	SCV004931132	pathogenic	Familial cancer of breast	2024-01-05	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.