ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1253A>G (p.Asp418Gly) (rs754898711)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482366 SCV000573497 uncertain significance not provided 2017-02-20 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1253A>G at the cDNA level, p.Asp418Gly (D418G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Asp418Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Asp418Gly occurs at a position that is not conserved and is located in the region of interaction with EXO1 (UniProt). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict this variant to create a new splice donor site and lead to abnormal splicing. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether MLH1 Asp418Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000572056 SCV000662066 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-27 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000572056 SCV000689796 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Mendelics RCV000987171 SCV001136404 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing

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