ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.1703G>T (p.Arg568Ile) (rs200381392)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129176 SCV000183911 likely benign Hereditary cancer-predisposing syndrome 2018-11-16 criteria provided, single submitter clinical testing Other data supporting benign classification;In silico models in agreement (benign) ;No disease association in small case-control study;Co-occurence with mutation in same gene (phase unknown)
GeneDx RCV000416037 SCV000209690 uncertain significance not provided 2018-12-24 criteria provided, single submitter clinical testing This variant is denoted ATM c.1703G>T at the cDNA level, p.Arg568Ile (R568I) at the protein level, and results in the change of an Arginine to an Isoleucine (AGA>ATA). This variant was observed in an individual with a personal and/or family history suggestive of Hereditary Breast and Ovarian Cancer (Cock-Rada 2018). ATM Arg568Ile was also identified in individuals with melanoma, breast, endometrial, and prostate cancer, as well as unaffected controls (Tung 2015, Decker 2017, Paulo 2018, Pritchard 2018, Yehia 2018). This variant was found to co-occur with an ATM frameshift variant in a patient with early-onset rectal cancer (Yurgelun 2017). ATM Arg568Ile was observed at an allele frequency of 0.34% (34/10,148) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether ATM Arg568Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000195658 SCV000254062 benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000416037 SCV000493325 uncertain significance not provided 2016-08-01 criteria provided, single submitter clinical testing
Color RCV000129176 SCV000537515 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-08 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515396 SCV000611346 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2017-05-23 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000855571 SCV000694193 likely benign not specified 2019-02-08 criteria provided, single submitter clinical testing Variant summary: ATM c.1703G>T (p.Arg568Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 276984 control chromosomes, predominantly at a frequency of 0.0034 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in ATM causing Breast Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.1703G>T has been reported in the literature in individuals affected with Colorectal cancer or prostate cancer (Yurgelun_2016, Paulo_2018). These reports do not provide unequivocal conclusions about association of the variant with Breast Cancer. Co-occurrences with other pathogenic/likely pathogenic variants have been reported (ATM c.8934_8935del, p.E2979Afs*9; CHEK2 c.1283C>T, p.Ser428Phe), providing supporting evidence for a benign role. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (7x VUS, 1x benign). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000195658 SCV000799739 uncertain significance Ataxia-telangiectasia syndrome 2018-05-03 criteria provided, single submitter clinical testing
Mendelics RCV000195658 SCV000838492 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000195658 SCV001266058 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.

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