Submissions for variant NM_000051.4(ATM):c.8741T>C (p.Ile2914Thr)

gnomAD frequency: 0.00001  dbSNP: rs780303327

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000167039	SCV000217863	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-10	criteria provided, single submitter	clinical testing	The p.I2914T variant (also known as c.8741T>C), located in coding exon 59 of the ATM gene, results from a T to C substitution at nucleotide position 8741. The isoleucine at codon 2914 is replaced by threonine, an amino acid with similar properties. This alteration was detected in 1/2531 breast cancer cases and not in 2245 controls (Tavtigian SV, Am. J. Hum. Genet. 2009 Oct; 85(4):427-46). This alteration was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J Med Genet, 2016 06;53:366-76). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Counsyl	RCV000668579	SCV000793205	uncertain significance	Ataxia-telangiectasia syndrome	2017-08-04	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000668579	SCV000957651	uncertain significance	Ataxia-telangiectasia syndrome	2023-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2914 of the ATM protein (p.Ile2914Thr). This variant is present in population databases (rs780303327, gnomAD 0.009%). This missense change has been observed in individual(s) with early onset and/or familial breast cancer (PMID: 19347964). ClinVar contains an entry for this variant (Variation ID: 187320). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV001507797	SCV001713589	uncertain significance	not provided	2019-12-27	criteria provided, single submitter	clinical testing
GeneDx	RCV001507797	SCV002599641	uncertain significance	not provided	2023-09-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with breast cancer in published literature (Tavtigian et al., 2009; Renault et al., 2022); This variant is associated with the following publications: (PMID: 19781682, 21787400, 20346647, 19347964, 26787654, 35365198, 23532176, 36243179)
Fulgent Genetics, Fulgent Genetics	RCV002485037	SCV002803863	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-04-26	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003468798	SCV004212024	uncertain significance	Familial cancer of breast	2023-04-09	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000167039	SCV004361924	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-28	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2914 of the ATM protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals with breast cancer (PMID: 19781682, 35365198). This variant has been identified in 5/282850 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV004596095	SCV005089833	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000668579	SCV001452580	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing