ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1774A>G (p.Ser592Gly)

dbSNP: rs2125984638
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001367513 SCV001563865 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-05-12 criteria provided, single submitter clinical testing 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 not expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 1058380). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 592 of the MLH1 protein (p.Ser592Gly).
Color Diagnostics, LLC DBA Color Health RCV001525260 SCV001735312 uncertain significance Hereditary cancer-predisposing syndrome 2021-01-11 criteria provided, single submitter clinical testing This missense variant replaces serine with glycine at codon 592 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.
Ambry Genetics RCV001525260 SCV002711870 uncertain significance Hereditary cancer-predisposing syndrome 2021-12-14 criteria provided, single submitter clinical testing The p.S592G variant (also known as c.1774A>G), located in coding exon 16 of the MLH1 gene, results from an A to G substitution at nucleotide position 1774. The serine at codon 592 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV004006808 SCV004843212 uncertain significance Lynch syndrome 2023-04-15 criteria provided, single submitter clinical testing This missense variant replaces serine with glycine at codon 592 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The 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.
GenomeConnect - Invitae Patient Insights Network RCV001535584 SCV001749579 not provided Mismatch repair cancer syndrome 1; Colorectal cancer, hereditary nonpolyposis, type 2 no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 09-24-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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