ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.6795C>T (rs3218699)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122878 SCV000166136 likely benign Ataxia-telangiectasia syndrome 2020-12-07 criteria provided, single submitter clinical testing
GeneDx RCV000212049 SCV000167053 benign not specified 2014-01-22 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 RCV000123710 SCV000212931 likely benign Hereditary cancer-predisposing syndrome 2014-07-07 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 RCV000122878 SCV000367065 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 RCV000123710 SCV000537473 likely benign Hereditary cancer-predisposing syndrome 2015-04-14 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000212049 SCV000593489 likely benign not specified 2017-04-10 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679140 SCV000805608 likely benign not provided 2017-01-06 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212049 SCV000916583 likely benign not specified 2018-06-18 criteria provided, single submitter clinical testing Variant summary: ATM c.6795C>T 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 0.00021 in 273300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.6795C>T, has been reported in the literature with limited information (Bernstein_2010, Pettitt_2001). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (3x) and uncertain signifncance (1x). Based on the evidence outlined above, the variant was classified as likely benign.
Athena Diagnostics Inc RCV000679140 SCV001143120 likely benign not provided 2019-07-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286938 SCV001473567 likely benign none provided 2020-04-24 criteria provided, single submitter clinical testing
Natera, Inc. RCV000122878 SCV001466202 likely benign Ataxia-telangiectasia syndrome 2020-04-03 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356930 SCV001552225 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The ATM p.Phe2265= variant was identified in 11 of 30,384 proband chromosomes (frequency: 0.0004) from individuals or families with breast cancer and was present in 8 of 10,976 control chromosomes (frequency: 0.0007) from healthy individuals (Bernstein 2010, Decker 2017). The variant was identified in dbSNP (rs3218699) as “with uncertain significance, other allele” and ClinVar (classified as likely benign by Color, Ambry Genetics, Invitae and 3 other submitters, benign by GeneDx and uncertain significance by Illumina). The variant was not identified in LOVD 3.0. The variant was identified in control databases in 57 of 278,902 chromosomes at a frequency of 0.0002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 49 of 128,014 chromosomes (freq: 0.0004), Other in 2 of 7164 chromosomes (freq: 0.0003), Latino in 3 of 35,362 chromosomes (freq: 0.00009), African in 2 of 24,802 chromosomes (freq: 0.00008), Finnish in 1 of 22,828 chromosomes (freq: 0.00004), while the variant was not observed in the Ashkenazi Jewish, East Asian and South Asian populations. The p.Phe2265= 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. The variant occurs at a non-highly conserved nucleotide 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.

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