ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.85G>T (p.Ala29Ser) (rs63750656)

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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 RCV000132377 SCV000187468 pathogenic Hereditary cancer-predisposing syndrome 2017-08-23 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Good segregation with disease (lod 1.5-3 = 5-9 meioses),Deficient protein function in appropriate functional assay(s)
Counsyl RCV000662773 SCV000785574 uncertain significance Lynch syndrome II 2017-09-26 criteria provided, single submitter clinical testing
GeneDx RCV000767178 SCV000279067 uncertain significance not provided 2018-11-27 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.85G>T at the cDNA level, p.Ala29Ser (A29S) at the protein level, and results in the change of an Alanine to a Serine (GCT>TCT). This variant has been consistently reported with MLH1 c.-27C>A as a haplotype, observed in many individuals with a personal and/or family history of colorectal cancer (Wagner 2003, Raevaara 2005, Hitchins 2011, Ward 2013, Kwok 2014). This variant, studied in isolation using various functional studies, was found to exhibit a dominant mutator effect, and with regard to MLH1 protein expression, mismatch repair activity, protein localization and PMS2 interaction, showed no significant difference when compared to wild type (Raevaara 2005, Takahashi 2007). Although the combined MLH1 c.-27C>A and Ala29Ser haplotype has been shown to result in promoter methylation and decreased promoter activity, when examined independently, MLH1 Ala29Ser by itself was found to result in promoter activity similar to wild type (Hitchins 2011). MLH1 Ala29Ser was not observed in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (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 Ala29Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000697498 SCV000826113 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-02 criteria provided, single submitter clinical testing This sequence change replaces alanine with serine at codon 29 of the MLH1 protein (p.Ala29Ser). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported on the same chromosome with the c.-27C>A promoter MLH1 variant in numerous individuals affected with Lynch syndrome (PMID: 21840485, 16083711, 22878509, 12658575), and was reported to segregate with disease in several families (PMID: 24084575, 21840485). ClinVar contains an entry for this variant (Variation ID: 90397). Experimental studies have shown that this missense change alone does not affect protein expression, mismatch repair activity, localization, and interaction with the PMS2 protein (PMID: 17510385, 16083711). While the combined c.-27C>A and p.Ala29Ser haplotype decreases the promoter activity, this variant alone exhibits the promoter activity similar to wild-type (PMID: 21840485). 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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201970 SCV000257118 uncertain significance not specified no assertion criteria provided clinical testing

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