Submissions for variant NM_000051.4(ATM):c.411C>A (p.Tyr137Ter)

dbSNP: rs756160533

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001021902	SCV001183577	pathogenic	Hereditary cancer-predisposing syndrome	2019-01-23	criteria provided, single submitter	clinical testing	The p.Y137* pathogenic mutation (also known as c.411C>A), located in coding exon 4 of the ATM gene, results from a C to A substitution at nucleotide position 411. This changes the amino acid from a tyrosine to a stop codon within coding exon 4. 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	RCV001390152	SCV001591787	pathogenic	Ataxia-telangiectasia syndrome	2020-02-07	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in ATM are known to be pathogenic (PMID: 23807571, 25614872). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has not been reported in the literature in individuals with ATM-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr137*) in the ATM gene. It is expected to result in an absent or disrupted protein product.
Myriad Genetics, Inc.	RCV004030813	SCV004931655	pathogenic	Familial cancer of breast	2024-01-09	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356735	SCV001551985	likely pathogenic	Carcinoma of colon		no assertion criteria provided	clinical testing	The ATM p.Tyr137* variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, or LOVD 3.0 databases. The variant was also not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.411C>A variant leads to a premature stop codon at amino acid position 137, located in exon 5 of a total of 63 exons for ATM. This variant is predicted to lead to a truncated protein and loss of function. Loss of function variants of the ATM gene are an established mechanism of disease in ATM associated cancers. Other truncating variants identified within the same ATM near this loci p.Tyr137 are reported in ClinVar as pathogenic. Computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.