Submissions for variant NM_000051.4(ATM):c.3256C>T (p.Arg1086Cys)

gnomAD frequency: 0.00001  dbSNP: rs201780199

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000220781	SCV000278503	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	The p.R1086C variant (also known as c.3256C>T), located in coding exon 21 of the ATM gene, results from a C to T substitution at nucleotide position 3256. The arginine at codon 1086 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration was identified in 1/1207 cases of French women diagnosed with breast cancer who had a sister with breast cancer and were BRCA1 and BRCA2 negative and 0/1199 general population controls (Girard E et al. Int J Cancer, 2019 04;144:1962-1974). This alteration was also reported in 1/5560 prostate cancer cases and in 0/3353 controls of European ancestry (Karlsson Q et al. Eur Urol Oncol, 2021 Aug;4:570-579). This alteration was 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, and cysteine is the reference amino acid in other 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	RCV000462986	SCV000546897	likely benign	Ataxia-telangiectasia syndrome	2024-01-06	criteria provided, single submitter	clinical testing
Mendelics	RCV003491988	SCV000838519	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757014	SCV000885037	uncertain significance	not provided	2018-03-20	criteria provided, single submitter	clinical testing	The ATM c.3256C>T; p.Arg1086Cys variant (rs201780199, ClinVar variant ID 234020), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.003% (identified on 8 out of 276,914 chromosomes). The arginine at position 1086 is moderately conserved, considering 9 species, and computational analyses of the effects of the p.Arg1086Cys variant on protein structure and function do not predict a deleterious effect (SIFT: tolerated, PolyPhen-2: benign). Based on the available information, the clinical significance of the p.Arg1086Cys variant cannot be determined with certainty.
Color Diagnostics, LLC DBA Color Health	RCV000220781	SCV000904601	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-14	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine 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. In a large international case-control study, this variant was reported in 1/60466 breast cancer cases and 3/53461 controls (OR=0.295, 95%CI 0.031 to 2.833, p-value=0.347; PMID: 33471991). This variant has been identified in 9/282596 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.
Illumina Laboratory Services, Illumina	RCV000462986	SCV001266175	uncertain significance	Ataxia-telangiectasia syndrome	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV000757014	SCV002512884	uncertain significance	not provided	2022-04-26	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 an individual with breast cancer (Girard 2019); This variant is associated with the following publications: (PMID: 27159395, 30303537)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330592	SCV004038705	uncertain significance	not specified	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: ATM c.3256C>T (p.Arg1086Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251210 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3256C>T has been reported in the literature as a monoallelic genotype or with unspcified zygosity in individuals affected with breast cancer or with family history of breast cancer (e.g. Girard_2019, Guindalini_2022), in verified BRCA1/2-negative breast cancer and/or ovarian cancer, including triple-negative breast cancer (e.g. Gomes_2020, Zanti_2020), prostate cancer (e.g. Karlsson_2021), or as a compound heterozygous genotype with the second variant reported as VUS in pancreatic ductal adenocarcinoma (e.g. Yin_2022). Most cases occurred in settings of multi-gene panel testing, were often reported as a VUS, with all cases without evidence of causality. These report(s) do not provide unequivocal conclusions about association of the variant with Breast Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33128190, 33436325, 30303537, 35171259, 35264596, 28652578, 33120919). Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as uncertain significance (n=7), or likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003469092	SCV004209440	uncertain significance	Familial cancer of breast	2023-09-15	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000462986	SCV002082240	uncertain significance	Ataxia-telangiectasia syndrome	2020-07-17	no assertion criteria provided	clinical testing