Submissions for variant NM_000051.4(ATM):c.549_550del (p.His183fs)

dbSNP: rs730881297

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000159626	SCV000209613	pathogenic	not provided	2014-08-27	criteria provided, single submitter	clinical testing	This deletion of 2 nucleotides in ATM is denoted c.549_550delTA at the cDNA level and p.His183GlnfsX6 (H183QfsX6) at the protein level. The normal sequence, with the bases that are deleted in brackets, is TTCA[TA]GAGT. The deletion causes a frameshift, which changes a Histidine to a Glutamine at codon 183, and creates a premature stop codon at position 6 of the new reading frame. Although this variant has not, to our knowledge, been reported in the literature, it is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. we consider this variant to be pathogenic.The presence of
Labcorp Genetics (formerly Invitae), Labcorp	RCV000471869	SCV000546981	pathogenic	Ataxia-telangiectasia syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.His183Glnfs*6) 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 colon cancer (PMID: 26681312). ClinVar contains an entry for this variant (Variation ID: 181868). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000572101	SCV000667976	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-15	criteria provided, single submitter	clinical testing	The c.549_550delTA pathogenic mutation, located in coding exon 5 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 549 to 550, causing a translational frameshift with a predicted alternate stop codon (p.H183QFS*6). This alteration was identified in 1/10030 patients referred for hereditary cancer panel testing (Susswein LR et al. Genet. Med., 2016 Aug;18:823-32). 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.
Baylor Genetics	RCV003462066	SCV004216238	likely pathogenic	Familial cancer of breast	2021-05-25	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003462066	SCV004930634	pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a frameshift predicted to result in premature protein truncation.
PreventionGenetics, part of Exact Sciences	RCV004739493	SCV005341883	pathogenic	ATM-related disorder	2024-03-14	no assertion criteria provided	clinical testing	The ATM c.549_550delTA variant is predicted to result in a frameshift and premature protein termination (p.His183Glnfs*6). This variant has been reported in an individual with colon cancer (Table S1. Susswein et al 2016. PubMed ID: 26681312). 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 or likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/181868/). Frameshift variants in ATM are expected to be pathogenic. In summary, this variant is interpreted as pathogenic.