Submissions for variant NM_000051.4(ATM):c.5319_5319+8delinsTGTTTG

dbSNP: rs1064792939

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV005208568	SCV000546796	uncertain significance	Ataxia-telangiectasia syndrome	2021-02-04	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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 disease. ClinVar contains an entry for this variant (Variation ID: 407532). This variant is not present in population databases (ExAC no frequency). This variant is a complex sequence change involving the donor splice site of intron 35. It results in a nucleotide substitution at the last nucleotide of exon 35 of the ATM coding sequence, which is part of the consensus splice site for this exon.
GeneDx	RCV000482571	SCV000566401	uncertain significance	not provided	2018-02-02	criteria provided, single submitter	clinical testing	This variant is denoted ATM c.5319_5319+8delGGTCTCTTAinsTGTTTG at the cDNA level. The surrounding sequence is GAAAAAA[delGgtctctta][insTgtttg]agta, where the capital letters are exonic and lower case are intronic. Although this combined deletion and insertion spans the intron/exon boundary including the canonical splice site, a 'GT' is retained at the canonical +1 and +2 positions. In silico analyses, which include splice predictors and evolutionary conservation, are uninformative in their assessment as to whether or not the variant is damaging; therefore, in the absence of RNA or functional studies, the actual effect of this variant is unknown. ATM c.5319_5319+8delGGTCTCTTAinsTGTTTG has not, to our knowledge, been reported in the literature as pathogenic or benign. This variant was not observed in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether this variant is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV002348306	SCV002646792	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-31	criteria provided, single submitter	clinical testing	The c.5319_5319+8delinsTGTTTG variant results from a deletion of 9 nucleotides and insertion of 6 nucleotides between positions c.5319 and c.5319+8. This variant involves the last nucleotide of coding exon 35 of the ATM gene but maintains the sequence of the canonical positions at this donor site. The last nucleotide is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native donor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV004567993	SCV005053051	uncertain significance	Familial cancer of breast	2023-11-02	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004567993	SCV005898908	likely pathogenic	Familial cancer of breast	2024-10-08	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].