Submissions for variant NM_000051.4(ATM):c.9023G>A (p.Arg3008His)

gnomAD frequency: 0.00001  dbSNP: rs587781894

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130230	SCV000185070	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-29	criteria provided, single submitter	clinical testing	The p.R3008H variant (also known as c.9023G>A), located in coding exon 62 of the ATM gene, results from a G to A substitution at nucleotide position 9023. The arginine at codon 3008 is replaced by histidine, an amino acid with highly similar properties. In one study, this alteration was reported in conjunction with a nonsense ATM mutation in a child with ataxia-telangiectasia (A-T). In the same study, this alteration was detected in 1/122 breast cancer patients with a family history of both breast cancer and a hematological malignancy and was not seen in any of the 186 control patients (Paglia LL et al. Breast Cancer Res.Treat. 2010; 119:443-52). This variant has also been reported in conjunction with a frameshift ATM mutation in a Norwegian patient with A-T (Strand J et al. Front Immunol, 2020 Jul;11:1417). This variant was also reported in conjunction with a leaky splice site variant in ATM in a 45 year old patient and in three siblings with variant type A-T (Schon K et al. Ann. Neurol., 2019 02;85:170-180; Caputi C et al. Mov Disord Clin Pract, 2023 Jan;10:124-129). A functional study performed in p.R3008H expressing mice demonstrated the mice are viable, immunodeficient, and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared to Atm-/- controls; the mutant animals also displayed cell cycle checkpoint defects and reduced lymphocyte development (Milanovic M et al. Cancer Res, 2021 Jan;81:426-437). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000196159	SCV000253673	pathogenic	Ataxia-telangiectasia syndrome	2024-01-19	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 3008 of the ATM protein (p.Arg3008His). This variant is present in population databases (rs587781894, gnomAD 0.004%). This missense change has been observed in individual(s) with ataxia-telangiectasia and/or personal or family history of breast, ovarian, and/or colon cancer (PMID: 2166257, 19404735, 21665257, 29752822, 31118792, 32754152). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 141634). 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. This variant disrupts the p.Arg3008 amino acid residue in ATM. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9872980, 10817650, 12552566, 15101044, 18573109, 19431188). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000254719	SCV000322217	likely pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Observed in a patient with ataxia telangiectasia who harbored an ATM truncating variant, but information regarding phase (variants in cis or trans) was not provided (PMID: 21665257); Observed in the heterozygous state in individuals with a personal or family history of breast, colorectal, and other cancers (PMID: 19404735, 31118792, 29752822, 33436325); Published functional studies demonstrate a damaging effect: reduced or normal ATM protein expression, deficient p21 induction, and reduced ATM kinase activity (PMID: 11756177, 33239428, 23585524); In silico analysis supports that this missense variant has 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: 17968022, 12697903, 25742471, 12149228, 28152038, 27586204, 29752822, 30620386, 19404735, 22529920, 10397742, 11756177, 23585524, 21933854, 27714650, 23103869, 26536348, 25925381, 26205736, 29316426, 29922827, 29946849, 29866652, 27194209, 28652578, 30549301, 30855176, 31118792, 32754152, 33332384, 33436325, 32873698, 34771661, 33598286, 33280026, 35480123, 33239428, 34556870, 34151669, 35347810, 31263571, 33536256, Villaruz2022[Abstract], 23532176, 21665257, 35264596, 35886069)
Color Diagnostics, LLC DBA Color Health	RCV000130230	SCV000687872	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-21	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 3008 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). Mouse models carrying this variant were immunodeficient and displayed spontaneous craniofacial abnormalities and delayed lymphomagenesis compared with wild type controls (PMID: 33239428). This variant has been reported in individuals affected with ataxia-telangiectasia (PMID: 21665257, 30549301). This variant has also been reported in individuals with a personal and/or family history of breast cancer or colorectal cancer (PMID: 19404735, 29752822, 31118792). In addition, a different variant affecting the same amino acid position (p.Arg3008Cys) is considered to be disease-causing (ClinVar variation ID: 142187), suggesting that arginine at this position is important for protein structure and function. This variant has been identified in 2/246168 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Mendelics	RCV000196159	SCV000838623	likely pathogenic	Ataxia-telangiectasia syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002281955	SCV001360469	likely pathogenic	Malignant tumor of breast	2022-08-11	criteria provided, single submitter	clinical testing	Variant summary: ATM c.9023G>A (p.Arg3008His) results in a non-conservative amino acid change located in the Phosphatidylinositol 3-/4-kinase, catalytic domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251410 control chromosomes (gnomAD). c.9023G>A has been reported in the literature in individuals affected with Breast Cancer (Li_2018, Pagila_2010), Ataxia-Telangiectasia (Micol_2011, Schon_2019), colorectal cancer (Gong_2019), along with multiple somatic occurrences (Austen_2007, Camacho_2002, Chang_2015, Fang_2003, Gronbaek_2002, Ida_2019, Navrkalova_2013, Schaffner_1999). These data indicate that the variant is likely to be associated with disease. In addition, another missense change at this position, R3008C, has been highly reported to be associated with cancer and A-T. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions (evaluation after 2014) cite the variant as likely pathogenic (n=7)/pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Spanish ATM Cancer Susceptibility Variant Interpretation Working Group	RCV000130230	SCV001911494	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-06-17	criteria provided, single submitter	clinical testing	The c.9023G>A (p.Arg3008His) variant has an allele frequency of 0.00075%, (2/268,268 alleles) in the gnomAD v2.1.1 non-cancer dataset, since it has been found once in the Finnish subpopulation (1/25,106) and once in the European non-Finnish subpopulation (1/118,102 alleles) (PM2; http://gnomad.broadinstitute.org). It is not predicted to lead to a splicing alteration according to SPiCE, and no splicing site is created or activated according to at least 3 splicing predictors of the set SpliceSiteFinderlike - MaxEntScan - NNSplice - GeneSplicer. However, the in silico protein effect prediction for this missense variant is inconclusive. On the other side, it is located at the somatic mutational hotspot codon p.Arg3008 (PM1). Moreover, the pathogenic variant c.9022C>T p.(Arg3008Cys) is located in the same codon. This variant was detected in two ataxia-telangiectasia probands (PS4_Moderate; PMID: 30549301, 21665257). Therefore, this variant meets criteria to be classified as likely pathogenic. Adapted ACMG/AMP rules applied as defined by the Spanish ATM working group: PM2 + PM1 + PS4_Moderate (PMID: 33280026).
Sema4, Sema4	RCV000130230	SCV002530658	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-09-02	criteria provided, single submitter	curation
Baylor Genetics	RCV003467134	SCV004209419	pathogenic	Familial cancer of breast	2023-09-21	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV000196159	SCV002083232	likely pathogenic	Ataxia-telangiectasia syndrome	2020-09-02	no assertion criteria provided	clinical testing
Laboratory for Genotyping Development, RIKEN	RCV003162582	SCV002758115	pathogenic	Gastric cancer	2021-07-01	no assertion criteria provided	research