Submissions for variant NM_000051.4(ATM):c.6554T>C (p.Ile2185Thr)

gnomAD frequency: 0.00003  dbSNP: rs779611511

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000236528	SCV000293970	uncertain significance	not provided	2023-06-29	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 30287823, 33608381, 28779002, 35406559, 23532176, 35264596, 35171259, 33471991)
Ambry Genetics	RCV000571895	SCV000660482	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	The p.I2185T variant (also known as c.6554T>C), located in coding exon 44 of the ATM gene, results from a T to C substitution at nucleotide position 6554. The isoleucine at codon 2185 is replaced by threonine, an amino acid with similar properties. This alteration has been reported in 1/13087 breast cancer cases and 0/5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 Nov;54:732-741). In another study, this variant was reported in 2/60,466 breast cancer cases and in 5/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In a case control study using individuals of Japanese ancestry, this alteration was not detected in 7051 unselected female breast cancer patients,11241 female controls, or 53 male breast cancer patients and was observed with an allele frequency of 0.0001 in 12490 male controls (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This alteration was also detected in a cohort of 1663 Brazilian breast cancer patients who underwent hereditary multigene panel testing (Guindalini RSC et al. Sci Rep, 2022 Mar;12:4190). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000686103	SCV000813606	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-28	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 2185 of the ATM protein (p.Ile2185Thr). This variant is present in population databases (rs779611511, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, pancreatic cancer, and/or prostate cancer (PMID: 28779002, 33608381, 35171259, 35264596). ClinVar contains an entry for this variant (Variation ID: 246421). 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 tolerated. 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.
Mendelics	RCV000686103	SCV000838577	uncertain significance	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000571895	SCV000904708	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 2185 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast cancer (PMID: 28779002, 33471991, 35264596) but has also been reported in a healthy control individuals (PMID: 30287823, 32980694, 33471991). In a large international case-control study, this variant was reported in 2/60466 breast cancer cases and 5/53461 controls (PMID: 33471991). This variant has also been identified in 6/282842 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.
Sema4, Sema4	RCV000571895	SCV002537969	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-09	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465602	SCV002760681	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002494680	SCV002797020	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2022-05-31	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003469189	SCV004210305	uncertain significance	Familial cancer of breast	2023-06-04	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000686103	SCV001458450	uncertain significance	Ataxia-telangiectasia syndrome	2020-09-16	no assertion criteria provided	clinical testing