Submissions for variant NM_000051.4(ATM):c.3257G>A (p.Arg1086His)

dbSNP: rs769857066

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000213977	SCV000278819	uncertain significance	not provided	2022-12-01	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; Identified in individuals with chronic lymphocytic leukemia, breast cancer, and head and neck squamous cell carcinoma (Lu et al., 2015; Tiao et al., 2017; Dorling et al., 2021) and in unaffected controls (Momozawa et al., 2018; Mizukami et al., 2020); This variant is associated with the following publications: (PMID: 26053404, 28652578, 26689913, 30287823, 32980694, 19781682, 33980423, 33471991)
Invitae	RCV000234243	SCV000282926	uncertain significance	Ataxia-telangiectasia syndrome	2024-01-30	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1086 of the ATM protein (p.Arg1086His). This variant is present in population databases (rs769857066, gnomAD 0.01%). This missense change has been observed in individual(s) with head and neck squamous cell carcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 234265). 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.
Ambry Genetics	RCV000575194	SCV000660457	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-07	criteria provided, single submitter	clinical testing	The p.R1086H variant (also known as c.3257G>A), located in coding exon 21 of the ATM gene, results from a G to A substitution at nucleotide position 3257. The arginine at codon 1086 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in both affected cancer cases and unaffected controls across numerous studies (Tiao G et al. Leukemia, 2017 Oct;31:2244-2247; Momozawa Y et al. Nat Commun, 2018 Oct;9:4083; Mizukami K et al. EBioMedicine, 2020 Oct;60:103033; Matejcic M et al. JCO Precis Oncol, 2020 Jan;4:32-43; Momozawa Y et al. J Natl Cancer Inst, 2020 Apr;112:369-376; Ece Solmaz A et al. Clin Breast Cancer, 2021 Dec;21:e647-e653; Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000575194	SCV000908263	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 1086 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, head and neck squamous cell carcinoma, and chronic lymphocytic leukemia (PMID: 26053404, 26689913, 33471991, 33980423; DOI: 10.5505/tjo.2022.3529) as well as unaffected individuals from breast cancer, pancreatic cancer, and prostate cancer case-control studies (PMID: 30287823, 31214711, 32980694). This variant has been identified in 6/251176 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	RCV000575194	SCV002535857	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-10	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002485436	SCV002786239	uncertain significance	Familial cancer of breast; Ataxia-telangiectasia syndrome	2021-07-23	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003338472	SCV004048167	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 1		criteria provided, single submitter	clinical testing	The missense variant in c.3257G>A (p.Arg1086His) in ATM gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. This variant has been reported to the ClinVar database as Uncertain Significance . The p.Arg1086His variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.002389% is reported in gnomAD. The amino acid Arg at position 1086 is changed to a His changing protein sequence and it might alter its composition and physico-chemical properties. The residue is conserved across species. The amino acid change p.Arg1086His in ATM is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The variant is predicted to be damaging by both SIFT and PolyPhen2. For these reasons, this variant has been classified as Uncertain Significance .
Baylor Genetics	RCV003463608	SCV004205124	uncertain significance	Familial cancer of breast	2024-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003463608	SCV005082894	likely benign	Familial cancer of breast	2024-05-14	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Natera, Inc.	RCV000234243	SCV002082251	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-27	no assertion criteria provided	clinical testing