ClinVar Miner

Submissions for variant NM_000051.3(ATM):c.3150T>C (p.Leu1050=) (rs3092859)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000122839 SCV000166097 benign Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162639 SCV000213076 likely benign Hereditary cancer-predisposing syndrome 2014-07-28 criteria provided, single submitter clinical testing
Color RCV000162639 SCV000682105 likely benign Hereditary cancer-predisposing syndrome 2015-08-07 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679110 SCV000805533 benign not specified 2017-08-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000679110 SCV000916614 benign not specified 2018-12-26 criteria provided, single submitter clinical testing Variant summary: The variant, ATM c.3150T>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 0.0016 in 277234 control chromosomes (gnomAD and publication), predominantly at a frequency of 0.009 within the Finnish subpopulation in the gnomAD database. The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 9 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 Finnish origin. The variant c.3150T>C has been reported in the literature in individuals affected with breast or ovarian cancer (Heikkinen_2005). This report, however does not provide unequivocal conclusions about association of the variant with Breast Cancer. In addition, an internal sample reports the variant to co-occur with a likely pathogenic RAD51C variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000122839 SCV001266173 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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