ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.1272T>C (p.Pro424=) (rs35578748)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122817 SCV000166074 benign Ataxia-telangiectasia syndrome 2020-12-03 criteria provided, single submitter clinical testing
GeneDx RCV000211959 SCV000209587 benign not specified 2014-09-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000159603 SCV000213198 likely benign Hereditary cancer-predisposing syndrome 2014-07-08 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Illumina Clinical Services Laboratory,Illumina RCV000122817 SCV000367028 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.
Color Health, Inc RCV000159603 SCV000537415 likely benign Hereditary cancer-predisposing syndrome 2015-07-16 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000211959 SCV000694176 likely benign not specified 2018-11-12 criteria provided, single submitter clinical testing Variant summary: ATM c.1272T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00028 in 274872 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in ATM causing Ataxia-Telangiectasia (0.00028 vs 0.004), allowing no conclusion about variant significance. c.1272T>C has been reported in the literature in an individual affected with Breast Cancer (Bernstein 2010), however this report does not provide unequivocal conclusions about association of the variant with Ataxia-Telangiectasia. Co-occurrence with another pathogenic variant have been reported (ATM c.6095G>A, in an internal sample), providing supporting evidence for a benign role. In addition, the variant was reported in 4 / 7325 European American women, who were older than 70 years of age, and never had cancer (in the FLOSSIES database). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 classifying the variant as benign, 2 calling it likely benign, and one as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics,PreventionGenetics RCV000588662 SCV000805494 likely benign not provided 2016-12-30 criteria provided, single submitter clinical testing
Mendelics RCV000122817 SCV001138463 likely benign Ataxia-telangiectasia syndrome 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000588662 SCV001148403 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000211959 SCV001469345 benign not specified 2020-03-18 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000211959 SCV001476944 benign not specified 2020-03-18 criteria provided, single submitter clinical testing
Natera, Inc. RCV000122817 SCV001461080 likely benign Ataxia-telangiectasia syndrome 2020-01-10 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355372 SCV001550244 benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Pro424Pro variant was not identified in the literature nor was it identified in the Genesight-COGR, Cosmic, and LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs35578748) “With other allele”, ClinVar (with conflicting interpretations of pathogenicity; submitters: benign by Invitae, GeneDx; likely benign by Ambry Genetics, Color Genomics; and uncertain significance by Illumina), Clinvitae (3x), and in control databases in 76 of 274872 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 1 of 23952 chromosomes (frequency: 0.00004), Other in 3 of 6438 chromosomes (frequency: 0.0004), Latino in 5 of 34362 chromosomes (frequency: 0.0001), European Non-Finnish in 54 of 126046 chromosomes (frequency: 0.0004), Ashkenazi Jewish in 4 of 10126 chromosomes (frequency: 0.0004), and South Asian in 9 of 30698 chromosomes (frequency: 0.0003). The variant was identified in our laboratory in 1 individual, co-occurring with a large pathogenic genomic deletion (EPCAM c.185-?_MSH2:c.366+?del) increasing the likelihood that the p.Pro424= variant does not have clinical significance. In addition, the p.Pro424= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000588662 SCV001808319 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000588662 SCV001906062 likely benign not provided no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000588662 SCV001956697 likely benign not provided no assertion criteria provided clinical testing

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