Submissions for variant NM_000051.4(ATM):c.1660del (p.Thr554fs)

dbSNP: rs876658572

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000221324	SCV000274001	pathogenic	Hereditary cancer-predisposing syndrome	2021-10-26	criteria provided, single submitter	clinical testing	The c.1660delA pathogenic mutation, located in coding exon 10 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 1660, causing a translational frameshift with a predicted alternate stop codon (p.T554Rfs*2). This alteration has been detected in 1/4112 breast cancer patients and 0/2399 healthy control individuals across numerous studies (Tavtigian S et al. Am J Hum Genet. 2009 Oct;85(4):427-46). This mutation has also been detected (in conjunction with ATM c.1027_1030delGAAA) in an individual with ataxia telangiectasia (Verhagen MM et al. Hum Mutat 2012 Mar;33(3):561-71). 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	RCV000802447	SCV000942279	pathogenic	Ataxia-telangiectasia syndrome	2023-11-25	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Thr554Argfs*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). 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 an individual affected with ataxia-telangiectasia (PMID: 10677309, 17393301, 19781682, 22213089, 30197789). ClinVar contains an entry for this variant (Variation ID: 230448). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003469002	SCV004210323	pathogenic	Familial cancer of breast	2024-02-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000221324	SCV004359665	pathogenic	Hereditary cancer-predisposing syndrome	2022-11-03	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 11 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 individuals affected with breast cancer (PMID: 10677309, 17393301, 19781682). This variant has also been observed in the compound heterozygous state in an individual affected with autosomal recessive ataxia-telangiectasia (PMID: 22213089), indicating that this variant contributes to disease. 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.	RCV003469002	SCV004933353	pathogenic	Familial cancer of breast	2024-01-16	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Natera, Inc.	RCV000802447	SCV001461009	pathogenic	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing