ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1730C>G (p.Ser577Trp)

dbSNP: rs56185292
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160541 SCV000211115 uncertain significance not provided 2014-04-28 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1730C>G at the cDNA level, p.Ser577Trp (S577W) at the protein level, and results in the change of a Serine to a Tryptophan (TCG>TGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Ser577Trp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Serine and Tryptophan differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Ser577Trp occurs at a position that is highly conserved across species and is located in the region of interaction with PMS2/MLH3/PMS1 (Raevaara 2005). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Ser577Trp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp RCV005089797 SCV005728935 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-03-12 criteria provided, single submitter clinical testing This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 577 of the MLH1 protein (p.Ser577Trp). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182528). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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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