ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.2016T>G (p.Cys672Trp)

gnomAD frequency: 0.00001  dbSNP: rs1312172811
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000553559 SCV000625116 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-07-03 criteria provided, single submitter clinical testing This missense change has been observed on the opposite chromosome (in trans) from a pathogenic variant in MLH1 in at least one individual (PMID: 23729658), which suggests that this variant may not be disease-causing. 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 455413). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.0009%). This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 672 of the MLH1 protein (p.Cys672Trp).
Ambry Genetics RCV000562503 SCV000673844 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-26 criteria provided, single submitter clinical testing The p.C672W variant (also known as c.2016T>G), located in coding exon 18 of the MLH1 gene, results from a T to G substitution at nucleotide position 2016. The cysteine at codon 672 is replaced by tryptophan, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health RCV000562503 SCV001352560 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-22 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tryptophan at codon 672 of the MLH1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. RT-PCR assays were reported to show no splicing defect due to this variant (PMID: 23729658). This variant been reported in a sample in the Universal Mutation Database in trans to a pathogenic MLH1 variant (PMID: 23729658). This variant has been identified in 1/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV003470707 SCV004192986 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-06-13 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004003718 SCV004843251 uncertain significance Lynch syndrome 2023-06-28 criteria provided, single submitter clinical testing This missense variant replaces cysteine with tryptophan at codon 672 of the MLH1 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. RT-PCR assays were reported to show no splicing defect due to this variant (PMID: 23729658). This variant been reported in a sample in the Universal Mutation Database in trans to a pathogenic MLH1 variant (PMID: 23729658). This variant has been identified in 1/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

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