ClinVar Miner

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

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Total submissions: 5
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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 Insufficient or conflicting evidence
Color RCV000572056 SCV000689796 uncertain significance Hereditary cancer-predisposing syndrome 2019-05-06 criteria provided, single submitter clinical testing
Mendelics RCV000987171 SCV001136404 uncertain significance Lynch syndrome II 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001039238 SCV001202758 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-01 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 418 of the MLH1 protein (p.Asp418Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs754898711, ExAC 0.001%). This variant has been observed in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 423761). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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