Submissions for variant NM_000051.4(ATM):c.4990G>T (p.Glu1664Ter)

dbSNP: rs1555103301

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001023376	SCV001185243	pathogenic	Hereditary cancer-predisposing syndrome	2019-02-15	criteria provided, single submitter	clinical testing	The p.E1664* pathogenic mutation (also known as c.4990G>T), located in coding exon 32 of the ATM gene, results from a G to T substitution at nucleotide position 4990. This changes the amino acid from a glutamic acid to a stop codon within coding exon 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.
Invitae	RCV001208228	SCV001379605	pathogenic	Ataxia-telangiectasia syndrome	2023-06-27	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 825347). This variant has not been reported in the literature in individuals affected with ATM-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu1664*) 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).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265926	SCV002548140	likely pathogenic	Familial prostate carcinoma	2022-05-24	criteria provided, single submitter	clinical testing	Variant summary: ATM c.4990G>T (p.Glu1664X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the 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. The variant was absent in 250852 control chromosomes. To our knowledge, no occurrence of c.4990G>T in individuals affected with ATM-related conditions and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
GeneDx	RCV002269328	SCV002553059	likely pathogenic	not provided	2022-01-21	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 significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge