ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3295G>A (p.Asp1099Asn) (rs372966951)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000168114 SCV000218770 uncertain significance Ataxia-telangiectasia syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1099 of the ATM protein (p.Asp1099Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs372966951, ExAC 0.03%). This variant has been reported in isolated individuals affected with breast cancer (PMID: 19781682, 21787400, 30093976) and colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 188196). 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 asparagine 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. 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 RCV000214286 SCV000278510 uncertain significance Hereditary cancer-predisposing syndrome 2020-09-25 criteria provided, single submitter clinical testing The p.D1099N variant (also known as c.3295G>A), located in coding exon 22 of the ATM gene, results from a G to A substitution at nucleotide position 3295. The aspartic acid at codon 1099 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in multiple breast cancer patients (Tavtigian SV et al. Am. J. Hum. Genet., 2009 Oct;85:427-46; Young EL et al. J. Med. Genet., 2016 06;53:366-76; Chan GHJ et al. Oncotarget, 2018 Jul;9:30649-30660). 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.
GeneDx RCV000590021 SCV000564627 uncertain significance not provided 2021-05-13 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 individuals with breast, colorectal, and other cancers (Tavtigian 2009, Yurgelun 2017, Chan SH 2018, Chan GHJ 2018); This variant is associated with the following publications: (PMID: 21787400, 26787654, 19781682, 25231023, 12697903, 28135145, 30455982, 30093976)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590021 SCV000694254 uncertain significance not provided 2017-07-21 criteria provided, single submitter clinical testing Variant summary: The ATM c.3295G>A (p.Asp1099Asn) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 4/85168 control chromosomes at a frequency of 0.000047, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). This variant has been reported in multiple affected individuals without strong evidence for causality. 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 RCV000214286 SCV000910978 likely benign Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing
Natera, Inc. RCV000168114 SCV001457136 uncertain significance Ataxia-telangiectasia syndrome 2020-09-16 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354999 SCV001549751 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Asp1099Asn variant was identified in 4 of 15480 proband chromosomes (frequency: 0.0003) from individuals or families with breast cancer and colorectal cancer and was not identified in 7694 control chromosomes from healthy individuals (Tavtigian 2009, Goldgar 2011, Yurgelun 2017). The variant was also identified in dbSNP (ID: rs372966951) as "With Uncertain significance allele", and in ClinVar (as uncertain significance by Ambry Genetics, Invitae, GeneDx, and Integrated Genetics). The variant was not identified in LOVD 3.0 database. The variant was identified in control databases in 7 of 239322 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 5374 chromosomes (freq: 0.0002), and South Asian in 6 of 30298 chromosomes (freq: 0.0002); it was not observed in the African, Latino, European, Ashkenazi Jewish, East Asian, or Finnish, populations. The p.Asp1099 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 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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