ClinVar Miner

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

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Total submissions: 14
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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 Co-occurence with mutation in same gene (phase unknown);In silico models in agreement (benign) ;No disease association in small case-control study;Other data supporting benign classification
GeneDx RCV000416037 SCV000209690 likely benign not provided 2021-03-17 criteria provided, single submitter clinical testing Observed in individuals with a personal and/or family history of melanoma, breast, ovarian, endometrial, colorectal or prostate cancer (Tung 2015, Decker 2017, Yurgelun 2017, Cock-Rada 2018, Paulo 2018, Pritchard 2018, Yehia 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26878173, 27997549, 28528518, 28135145, 28873162, 29641532, 28779002, 29684080, 28137924, 25186627, 29659569, 31658756)
Invitae RCV000195658 SCV000254062 benign Ataxia-telangiectasia syndrome 2020-12-07 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 Health, Inc RCV000129176 SCV000537515 likely benign Hereditary cancer-predisposing syndrome 2020-08-20 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
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV000515396 SCV001468410 uncertain significance Familial cancer of breast; Ataxia-telangiectasia syndrome 2020-09-30 criteria provided, single submitter clinical testing ATM NM_000051.3 exon11 p.Arg568Ile (c.1703G>T): This variant has been reported in the literature in 1 individual with rectal cancer (Yurgelun 2017 PMID:28135145). This variant is present in 0.3% (36/10366) of Ashkenazi Jewish alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/11-108122659-G-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:140916). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Of note, an additional variant at this same amino acid position (p.Arg568Lys) was identified in a patient with a history of cervix and breast cancer. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Athena Diagnostics Inc RCV000855571 SCV001880881 likely benign not specified 2020-09-21 criteria provided, single submitter clinical testing
Natera, Inc. RCV000195658 SCV001461082 uncertain significance Ataxia-telangiectasia syndrome 2020-01-11 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357003 SCV001552324 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Arg568Ile variant was identified in 1 of 170 proband chromosomes (frequency: 0.006) from individuals or families with breast and ovarian cancer (Cock-Rada 2017). The variant was also identified in the following databases: dbSNP (ID: rs200381392) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GenDx, Invitae) and Clinvitae. The variant was not identified in the COGR, Cosmic, MutDB, or LOVD 3.0 databases. The variant was identified in control databases in 54 of 276984 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency variant (Genome Aggregation Consortium Feb 27, 2017). The p.Arg568 residue is not conserved in mammals and four out of five 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 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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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