ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1559T>G (p.Val520Gly)

dbSNP: rs1200485334
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001012159 SCV001172580 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-07 criteria provided, single submitter clinical testing The p.V520G variant (also known as c.1559T>G) is located in coding exon 14 of the MLH1 gene. The valine at codon 520 is replaced by glycine, an amino acid with dissimilar properties. This change occurs in the first base pair of coding exon 14. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001318552 SCV001509259 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-05-09 criteria provided, single submitter clinical testing This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 520 of the MLH1 protein (p.Val520Gly). 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. Studies have shown that this missense change does not affect mRNA splicing (PMID: 19669161). 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 tolerated. ClinVar contains an entry for this variant (Variation ID: 819530). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 19669161). This variant is not present in population databases (gnomAD no frequency).
Preventiongenetics, part of Exact Sciences RCV003396596 SCV004103952 uncertain significance MLH1-related condition 2023-10-04 criteria provided, single submitter clinical testing The MLH1 c.1559T>G variant is predicted to result in the amino acid substitution p.Val520Gly. This variant has been reported in an individual with Lynch syndrome (Table 2, Betz et al. 2010. PubMed ID: 19669161). RT-PCR analysis indicates that this variant does not impact mRNA splicing (Table 2, Betz et al. 2010. PubMed ID: 19669161). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. It is interpreted as uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/819530/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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