Submissions for variant NM_000051.4(ATM):c.7983TGT[2] (p.Val2664del)

dbSNP: rs876660743

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000214450	SCV000278410	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-02-16	criteria provided, single submitter	clinical testing	The c.7989_7991delTGT variant (also known as p.V2664del) is located in coding exon 53 of the ATM gene. This variant results from an in-frame deletion of 3 nucleotides between positions 7989 to 7991. This results in the deletion of a valine residue at codon 2664. This alteration has been described in several patients with ataxia-telangiectasia (A-T), including being detected as a homozygous alteration and in conjunction with another pathogenic ATM mutation (Sandoval N et al. Hum Mol Genet. 1999 Jan;8(1):69-79; Castellvi-Bel S et al. Hum Mutat. 1999;14(2):156-62; Li A and Swift M et al. Am J Med Genet. 2000 May 29;92(3):170-7; Demuth I et al. Neurogenetics. 2011 Nov;12(4):273-82; Chen Z et al. Neurobiol Aging, 2013 Oct;34:2442.e11-7). In addition, functional assays have shown reduced levels of ATM protein expression and an absence of induced ATM kinase activity (Sandoval N et al. Hum Mol Genet. 1999 Jan;8(1):69-79; Scott SP et al. Proc Natl Acad Sci U S A. 2002 Jan 22;99(2):925-30). Based on internal structural analysis, this alteration is deleterious and is more untolerated than nearby pathogenic variants (Ambry internal data). Of note, this alteration is also designated as V2662del and V2663del in published literature. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al. PLoS ONE. 2012; 7(10):e46688). This amino acid position is well conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000475820	SCV000546816	likely pathogenic	Ataxia-telangiectasia syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This variant has been observed in individual(s) with ataxia-telangiectasia (A-T) as homozygous or co-occurring with another pathogenic ATM variant, as well as in A-T-affected individuals in whom no second variant was reported (PMID: 9887333, 10425038, 10817650, 21965147). 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. Experimental studies have shown that this variant affects ATM function (PMID: 11805335). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 233938). This variant is also known as V2662del, 7989delTGT and Del 3 at codon 2663. This variant is present in population databases (no rsID available, gnomAD 0.006%). This variant, c.7989_7991del, results in the deletion of 1 amino acid(s) of the ATM protein (p.Val2664del), but otherwise preserves the integrity of the reading frame.
GeneDx	RCV000478779	SCV000568335	likely pathogenic	not provided	2022-05-04	criteria provided, single submitter	clinical testing	In-frame deletion of 1 amino acid in a non-repeat region; Published functional studies demonstrate loss of protein expression that results in reduced kinase activity (Sandoval 1999, Scott 2002); In silico analysis supports a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21965147, 10817650, 10425038, 11805335, Erdem2019[article], 9887333)
Color Diagnostics, LLC DBA Color Health	RCV000214450	SCV001350124	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-08-31	criteria provided, single submitter	clinical testing	This variant causes an in-frame deletion of one amino acid in the ATM protein. Functional studies have reported that the variant protein displayed no detectable ATM kinase activity and failed to restore normal radiosensitivity in ATM-deficient cells (PMID: 9887333). This variant (also known as p.Val2662del in the literature) has been reported in the homozygous state or compound heterozygous state with an additional pathogenic ATM variant in individuals affected with ataxia telangiectasia (PMID: 9887333, 21965147), as well as in ataxia telangiectasia affected individuals whose second ATM mutation was not reported (PMID: 10425038, 10817650). This variant has been identified in 1/251250 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000478779	SCV001447812	likely pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469090	SCV004210127	pathogenic	Familial cancer of breast	2023-07-24	criteria provided, single submitter	clinical testing