ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1344G>T (p.Glu448Asp) (rs587779952)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115457 SCV000215076 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Co-occurence with a mutation in another gene that clearly explains a proband's phenotype,In silico models in agreement (benign),Insufficient or conflicting evidence,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000115457 SCV000684737 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-02 criteria provided, single submitter clinical testing
Counsyl RCV000412424 SCV000487997 uncertain significance Lynch syndrome II 2015-12-18 criteria provided, single submitter clinical testing
GeneDx RCV000212536 SCV000149366 uncertain significance not provided 2018-05-03 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1344G>T at the cDNA level, p.Glu448Asp (E448D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAG>GAT). This variant has been observed in at least one individual with familial colorectal cancer (Chubb 2015). MLH1 Glu448Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the region of interaction with EXO1 (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MLH1 Glu448Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000545514 SCV000625057 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 448 of the MLH1 protein (p.Glu448Asp). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is present in population databases (rs587779952, ExAC 0.001%). This variant has been reported in an individual affected with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 127612). 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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