Submissions for variant NM_000051.4(ATM):c.9145_9146del (p.Phe3049fs)

dbSNP: rs1555152058

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000628183	SCV000749076	likely pathogenic	Ataxia-telangiectasia syndrome	2023-11-13	criteria provided, single submitter	clinical testing	This sequence change results in a frameshift in the ATM gene (p.Phe3049Profs*13). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 8 amino acid(s) of the ATM protein and extend the protein by 4 additional amino acid residues. This variant is not present in population databases (gnomAD no frequency). This frameshift has been observed in individual(s) with ataxia-telangiectasia (PMID: 10817650). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 524412). This variant disrupts the FATC domain, which spans the last 33 amino acids of the ATM protein and is required for ATM kinase activity in response to DNA damage (PMID: 19781682, 16603769). While functional studies have not been performed to directly test the effect of this variant on ATM protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV001189989	SCV001357396	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-01-15	criteria provided, single submitter	clinical testing	This variant deletes 2 nucleotides in exon 63 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 Likely Pathogenic.
Ambry Genetics	RCV001189989	SCV002684811	uncertain significance	Hereditary cancer-predisposing syndrome	2020-01-22	criteria provided, single submitter	clinical testing	The c.9145_9146delTT variant, located in coding exon 62 of the ATM gene, results from a deletion of two nucleotides at nucleotide positions 9145 to 9146, causing a translational frameshift with a predicted alternate stop codon (p.F3049Pfs*13). This alteration has been reported in a compound heterozygous state in a cohort of families with ataxia telangiectasia (A-T) in the United States and Canada (Li A et al. Am. J. Med. Genet., 2000 May;92:170-7). Frameshifts are typically deleterious in nature, however, this frameshift occurs at the 3' terminus of ATM, is not expected to trigger nonsense-mediated mRNA decay, and results in the alteration of the last 8 amino acids and elongation of the protein by 4 amino acids. The exact functional impact of these altered/inserted amino acids is unknown at this time. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003465377	SCV004212217	likely pathogenic	Familial cancer of breast	2022-09-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003465377	SCV004931769	likely pathogenic	Familial cancer of breast	2024-02-06	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in the incorporation of abnormal amino acid sequence into the protein product and abnormal protein elongation. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 10817650, 16266405, 25614872, 15039971, 21965147].