ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1564C>T (p.Arg522Trp) (rs63751703)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216499 SCV000273158 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000216499 SCV000911976 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-06 criteria provided, single submitter clinical testing
Counsyl RCV000412186 SCV000488515 uncertain significance Lynch syndrome II 2016-04-15 criteria provided, single submitter clinical testing
GeneDx RCV000587282 SCV000569952 uncertain significance not provided 2018-04-30 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1564C>T at the cDNA level, p.Arg522Trp (R522W) at the protein level, and results in the change of an Arginine to a Tryptophan (CGG>TGG). This variant was observed in at least one individual with personal/family history suspicious for Lynch syndrome (Lagerstedt-Robinson 2016). Functional assays demonstrate this variant results in reduced protein expression but similar MMR activity compared with the wild-type (Hinrichsen 2013). MLH1 Arg522Trp was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the regions of interaction with EXO1 and PMS2/MLH3/PMS1 (Raevaara 2005, Kansikas 2011, Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Arg522Trp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587282 SCV000696116 uncertain significance not provided 2016-06-06 criteria provided, single submitter clinical testing Variant summary: The MLH1 c.1564C>T (p.Arg522Trp) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant was found in 4/121218 control chromosomes at a frequency of 0.000033, which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). In addition, multiple clinical diagnostic laboratories classified this variant as VUS, without evidence to independently evaluate. This variant, to our knowledge, has not been reported as a germ-line variant in affected individuals. One study showed this variant with protein expression level not significantly different from WT (Hinrichsen_2013). Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000195882 SCV000254354 uncertain significance Hereditary nonpolyposis colon cancer 2018-10-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with tryptophan at codon 522 of the MLH1 protein (p.Arg522Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs63751703, ExAC 0.006%). This variant has been reported in an individual affected with suspected Lynch syndrome (PMID: 27601186). ClinVar contains an entry for this variant (Variation ID: 216331). An experimental study has shown that this variant did not affect the mismatch repair activity of the MLH1 protein, and caused only a slight reduction in MLH1 expression (PMID: 23403630). 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.
PreventionGenetics RCV000587282 SCV000805952 uncertain significance not provided 2017-12-12 criteria provided, single submitter clinical testing

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