Submissions for variant NM_000249.3(MLH1):c.1460G>A (p.Arg487Gln) (rs587778917)

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Total submissions: 4

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000218037	SCV000275866	uncertain significance	Hereditary cancer-predisposing syndrome	2017-10-31	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
GeneDx	RCV000480533	SCV000571659	uncertain significance	not provided	2018-02-15	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1460G>A at the cDNA level, p.Arg487Gln (R487Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Arg487Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). MLH1 Arg487Gln 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 Arg487Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000630048	SCV000751004	uncertain significance	Hereditary nonpolyposis colon cancer	2018-06-27	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with glutamine at codon 487 of the MLH1 protein (p.Arg487Gln). The arginine residue is weakly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs587778917, ExAC 0.03%). This variant has not been reported in the literature in individuals with MLH1-related disease. ClinVar contains an entry for this variant (Variation ID: 89745). 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 glutamine 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. 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.
Color	RCV000218037	SCV000903938	likely benign	Hereditary cancer-predisposing syndrome	2016-10-16	criteria provided, single submitter	clinical testing

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