ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.202A>G (p.Ile68Val) (rs35389822)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000587881 SCV000149057 uncertain significance not provided 2021-07-07 criteria provided, single submitter clinical testing Not observed at a significant frequency in large population cohorts (Lek 2016); 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 cancer, pancreatic cancer, and other cancers as well as controls (Renwick 2006, Tavtigian 2009, Petereit 2013, Chaffee 2017, Pritchard 2018); This variant is associated with the following publications: (PMID: 27535533, 29641532, 30851065, 16832357, 28726808, 22529920, 19781682, 27720647, 24416720)
Ambry Genetics RCV000115148 SCV000185268 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-29 criteria provided, single submitter clinical testing The p.I68V variant (also known as c.202A>G), located in coding exon 3 of the ATM gene, results from an A to G substitution at nucleotide position 202. The isoleucine at codon 68 is replaced by valine, an amino acid with highly similar properties. This variant was identified in 1/302 patients with personal and family histories of pancreatic cancer (Chaffee KG et al. Genet. Med. 2018 01;20:119-127). This alteration has also been identified in unaffected control cohorts in multiple studies (Renwick A et al. Nat. Genet., 2006 Aug;38:873-5; Tavtigian SV et al. Am. J. Hum. Genet. 2009 Oct;85:427-46; Pritchard AL et al. PLoS ONE, 2018 Apr;13:e0194098). This amino acid position is not well conserved in available vertebrate species, and valine 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 RCV000199503 SCV000254067 uncertain significance Ataxia-telangiectasia syndrome 2020-10-13 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 68 of the ATM protein (p.Ile68Val). The isoleucine residue is moderately conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs35389822, ExAC 0.004%). This variant has been reported in individuals affected with pancreatic cancer or an undefined cancer (PMID: 28726808, 24416720), and an unaffected individual (PMID: 19781682). ClinVar contains an entry for this variant (Variation ID: 127344). 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 valine 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.
Fulgent Genetics,Fulgent Genetics RCV000515328 SCV000611348 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 RCV000587881 SCV000694207 uncertain significance not provided 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The ATM c.202A>G (p.Ile68Val) variant involves the alteration of a conserved nucleotide. Ile68 is not conserved across species and is not located in a known functional domain; 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/102164 control chromosomes at a frequency of 0.0000294, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005). The variant was identified in only one cancer patient reported in the literature, however, no clinical or co-segregation data was provided, thus its implication in this patients cancer diagnosis cannot be assessed (Petereit_2013). In addition, multiple clinical diagnostic laboratories classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000199503 SCV000791981 uncertain significance Ataxia-telangiectasia syndrome 2017-06-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115148 SCV000902983 likely benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000587881 SCV001143099 uncertain significance not provided 2019-01-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355668 SCV001550618 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The ATM p.Ile68Val variant was identified in 1 of 16,852 proband chromosomes (frequency: 0.00006) from an individual with cancer and was present in 1 of 4798 control chromosomes (frequency: 0.0002) from healthy individuals (Petereit 2013, Tavtigian 2009). The variant was identified in dbSNP (rs35389822) as “with uncertain significance allele and ClinVar (classified as uncertain significance by Invitae, Ambry Genetics, Counsyl, GeneDx and 2 other submitters; and as likely benign by Color). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 8 of 275,380 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 8 of 125,734 chromosomes (freq: 0.00006), while it was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish or South Asian populations. The p.Ile68 residue is conserved in mammals but not in more distantly related organisms however computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. 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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