ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.301G>A (p.Gly101Ser) (rs267607726)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075623 SCV000106625 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
GeneDx RCV000486320 SCV000565140 likely pathogenic not provided 2016-12-23 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.301G>A at the cDNA level, p.Gly101Ser (G101S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant has been reported in individuals with a personal history of colorectal cancer and/or Lynch syndrome (Parc 2003, Tournier 2008, De Lellis 2013, Tricarico 2016). One of these individuals who met Amsterdam criteria, and whose tumor was microsatellite high and demonstrated loss of MLH1 on mismatch repair immunohistochemistry (De Lellis 2013). Despite MLH1 and PMS2 protein expression levels similar to wild-type, in vitro functional assays demonstrate MLH1 Gly101Ser to have a significant loss of mismatch repair activity supporting a deleterious effect (Tricarico 2016).MLH1 Gly101Ser 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 Glycine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Gly101Ser occurs at a position that is conserved across species and is located within the ATPase and MLH domains and in ATP-binding and hydrolysis motif (Pang 1997, Raevaara 2005, Hardt 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, we consider MLH1 Gly101Ser to be a likely pathogenic variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502831 SCV000592346 uncertain significance not specified 2014-12-05 criteria provided, single submitter clinical testing
Invitae RCV001211883 SCV001383446 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-07-29 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 101 of the MLH1 protein (p.Gly101Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of Lynch syndrome (PMID: 12624141, 24278394, 18561205). ClinVar contains an entry for this variant (Variation ID: 90137). This variant has been reported to affect MLH1 protein function (PMID: 27629256). An ex vivo functional splicing assay has shown this variant does not affect mRNA splicing (PMID: 18561205). However, another splicing assay revealed this variant results in the loss of the use of an alternative splice site (PMID: 27629256). The clinical significance of this finding is unknown. 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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