ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1245T>G (p.Asp415Glu) (rs750563193)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000217953 SCV000279796 uncertain significance not provided 2016-12-16 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1245T>G at the cDNA level, p.Asp415Glu (D415E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAG). This variant has been reported in at least one individual undergoing hereditary cancer panel testing (Yorczyk 2015). MLH1 Asp415Glu 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 Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. MLH1 Asp415Glu occurs at a position that is not conserved and is located in the region of interaction with EXO1 (UniProt). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MLH1 Asp415Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568159 SCV000669604 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-14 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV000568159 SCV000684732 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-05 criteria provided, single submitter clinical testing
Invitae RCV001060734 SCV001225441 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-28 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 415 of the MLH1 protein (p.Asp415Glu). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs750563193, ExAC 0.01%). This variant has not been reported in the literature in individuals with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 234772). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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