Submissions for variant NM_000051.4(ATM):c.5549del (p.Leu1850fs)

dbSNP: rs876658287

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219889	SCV000273322	pathogenic	Hereditary cancer-predisposing syndrome	2021-04-21	criteria provided, single submitter	clinical testing	The c.5549delT pathogenic mutation, located in coding exon 36 of the ATM gene, results from a deletion of one nucleotide at nucleotide position 5549, causing a translational frameshift with a predicted alternate stop codon (p.L1850Yfs*67). This alteration has been reported in multiple individuals with Ataxia-Telangiectasia (Sandoval N et al, Hum. Mol. Genet. 1999 Jan; 8(1):69-79; Castellví-Bel S et al, Hum. Mutat. 1999; 14(2):156-62; Li A et al, Am. J. Med. Genet. 2000 May; 92(3):170-7; Maciejczyk M et al. Front Immunol, 2019 Sep;10:2322). Additionally, this alteration has been identified in individuals diagnosed with ovarian and pancreatic cancer (Carter NJ et al. Gynecol Oncol, 2018 12;151:481-488; Hu C et al. JCO Precis Oncol, 2018 Jul;2:). This variant was also reported in 1/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). 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	RCV000236989	SCV000292817	pathogenic	not provided	2020-01-30	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; Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Carter 2018); Not observed in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30322717, 10425038, 26556299, 16266405, 9887333, 10817650, 29625052, 26689913)
Counsyl	RCV000411540	SCV000486274	likely pathogenic	Ataxia-telangiectasia syndrome	2016-04-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000411540	SCV001206115	pathogenic	Ataxia-telangiectasia syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu1850Tyrfs*67) 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 (rs750992549, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with ataxia-telangiectasia (PMID: 9887333, 10817650, 16266405). This variant is also known as 5546delT. ClinVar contains an entry for this variant (Variation ID: 229942). For these reasons, this variant has been classified as Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000219889	SCV001344865	pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 1 nucleotide in exon 37 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 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.
Baylor Genetics	RCV003462418	SCV004216223	pathogenic	Familial cancer of breast	2024-01-20	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003462418	SCV004930351	pathogenic	Familial cancer of breast	2024-01-25	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
Institute of Human Genetics, University of Leipzig Medical Center	RCV003462418	SCV005368402	pathogenic	Familial cancer of breast	2024-08-22	criteria provided, single submitter	clinical testing	Criteria applied: PVS1,PM2_SUP, PM3_SUP