ClinVar Miner

Submissions for variant NM_005590.4(MRE11):c.120C>T (p.Leu40=) (rs1805364)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212552 SCV000211161 benign not specified 2013-11-06 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 RCV000160575 SCV000213020 likely benign Hereditary cancer-predisposing syndrome 2014-08-29 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.
Invitae RCV001080131 SCV000253440 likely benign Ataxia-telangiectasia-like disorder 2020-12-01 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000524512 SCV000744083 likely benign Ataxia-telangiectasia-like disorder 1 2017-01-04 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000524512 SCV000745567 likely benign Ataxia-telangiectasia-like disorder 1 2017-06-28 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000524512 SCV000746007 likely benign Ataxia-telangiectasia-like disorder 1 2016-01-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212552 SCV000917681 benign not specified 2018-12-21 criteria provided, single submitter clinical testing Variant summary: The variant MRE11A c.120C>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 0.00055 in 277082 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 9-folds higher than the estimated maximal expected allele frequency for a pathogenic variant in MRE11A causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05). However, it does need to be noted that there is a pseudogene present on chromosome 3. The variant c.120C>T has been reported in the literature in individuals affected with breast cancer (Damiola_2014, Young_2016). These reports however do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. 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. Based on the evidence outlined above, the variant was classified as benign.
Athena Diagnostics Inc RCV000857671 SCV001144536 benign not provided 2018-09-27 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000524512 SCV001271864 uncertain significance Ataxia-telangiectasia-like disorder 1 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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