Submissions for variant NM_000051.4(ATM):c.237del (p.Lys79fs)

dbSNP: rs730881303

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159632	SCV000209620	pathogenic	not provided	2023-06-06	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 at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 29922827, 26681312, 23807571, 25614872, 30639167)
Invitae	RCV000548948	SCV000622324	pathogenic	Ataxia-telangiectasia syndrome	2024-01-08	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Lys79Asnfs*37) 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 (rs730881303, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ovarian cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 181874). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000570996	SCV000660499	pathogenic	Hereditary cancer-predisposing syndrome	2021-06-09	criteria provided, single submitter	clinical testing	The c.237delA pathogenic mutation, located in coding exon 3 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 237, causing a translational frameshift with a predicted alternate stop codon (p.K79Nfs*37). This mutation was identified in trans with a second truncating allele in a child with AT (Susswein LR et al. Genet Med, 2016 08;18:823-32) and identified heterozygous an individual diagnosed with ovarian cancer (Susswein LR et al. Genet. Med. 2016 Aug;18:823-32). 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.
Color Diagnostics, LLC DBA Color Health	RCV000570996	SCV000687382	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 4 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 identified in 1/250502 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000548948	SCV000694219	likely pathogenic	Ataxia-telangiectasia syndrome	2017-03-03	criteria provided, single submitter	clinical testing	Variant summary: The ATM c.237delA (p.Lys79Asnfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATM protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Tyr171X, p.Arg2993X, p.Lys2756X, etc.). This variant is absent in 114158 control chromosomes from ExAC. This variant has previously been reported in one A-T patient in compound heterozygous state with p.Tyr124Ter (Minto et al. 2017; a conference meeting abstract) and in one ovarian cancer patient (Susswein_2015). One clinical diagnostic laboratory has classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic.
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000548948	SCV002061480	pathogenic	Ataxia-telangiectasia syndrome	2021-04-06	criteria provided, single submitter	clinical testing	PVS1, PM2, PM3
Baylor Genetics	RCV003467217	SCV004212245	pathogenic	Familial cancer of breast	2024-03-24	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003467217	SCV004932159	pathogenic	Familial cancer of breast	2024-01-08	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.