ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3242A>G (p.Asn1081Ser) (rs368111672)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130850 SCV000185748 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-17 criteria provided, single submitter clinical testing The p.N1081S variant (also known as c.3242A>G), located in coding exon 21 of the ATM gene, results from an A to G substitution at nucleotide position 3242. The asparagine at codon 1081 is replaced by serine, an amino acid with highly similar properties. This alteration has been reported with a carrier frequency of 0.00014 in 7051 unselected breast cancer patients and 0.00009 in 11241 female controls and 0.001 in 12490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was detected in a study of 27 Moroccan ataxia-telangiectasia (AT) patients and classified as a polymorphism based on observed frequency (3/54 alleles) and in silico predictions (Jeddane L et al. Neuromolecular Med. 2013 Jun;15:288-94). This alteration has also been reported in at least one subject in a study of 13087 breast cancer cases and 5488 control individuals in the UK (Decker B et al. J. Med. Genet., 2017 11;54:732-741). This amino acid position is not well conserved in available vertebrate species, and serine 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.
GeneDx RCV000588298 SCV000209719 uncertain significance not provided 2020-12-10 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in an individual with ataxia telangiectasia, co-occurring with unspecified biallelic ATM variants, as well as in individuals with breast cancer (Jeddane 2013, Decker 2017); This variant is associated with the following publications: (PMID: 23322442, 24325359, 28873162, 28779002, 30287823)
Invitae RCV000475427 SCV000546670 uncertain significance Ataxia-telangiectasia syndrome 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1081 of the ATM protein (p.Asn1081Ser). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs368111672, ExAC 0.1%). This variant has been observed as a polymorphism in an individual with ataxia-telangiectasia (PMID: 23322442). ClinVar contains an entry for this variant (Variation ID: 142046). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Fulgent Genetics,Fulgent Genetics RCV000515162 SCV000611358 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588298 SCV000694253 uncertain significance not provided 2017-02-23 criteria provided, single submitter clinical testing Variant summary: The ATM c.3242A>G (p.Asn1081Ser) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 26/121284 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.001334 (22/16494). This frequency is about 1 times the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. The variant was reported in the literature in one AT patient and was described as a polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Color Health, Inc RCV000130850 SCV000902741 likely benign Hereditary cancer-predisposing syndrome 2015-06-15 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588298 SCV001148414 uncertain significance not provided 2018-06-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354773 SCV001549467 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Asn1081Ser variant was identified in 4 of 14140 proband chromosomes (frequency: 0.0003) from Moroccan individuals or families with Ataxia-Telangiectasia and Japanese individuals or families with breast cancer, and was present in 2 of 22482 control chromosomes (frequency: 0.00009) from healthy individuals (Jeddane 2013, Momozawa 2018). The variant was also identified in dbSNP (ID: rs368111672) as "With Uncertain significance allele", and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, GeneDx, Fulgent Genetics and Integrated Genetics; and likley benign by Color), and LOVD 3.0 (3x as benign). The variant was identified in control databases in 50 of 276988 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24026 chromosomes (freq: 0.00004), Latino in 3 of 34416 chromosomes (freq: 0.00009), European Non-Finnish in 5 of 126520 chromosomes (freq: 0.00004), and South Asian in 41 of 30780 chromosomes (freq: 0.001) while not observed in the Other, Ashkenazi Jewish, East Asian, or Finnish populations. The p.Asn1081 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood that the variant impacts the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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