Total submissions: 7
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000223006 | SCV000276523 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-08 | criteria provided, single submitter | clinical testing | The p.Y625C variant (also known as c.1874A>G), located in coding exon 16 of the MLH1 gene, results from an A to G substitution at nucleotide position 1874. The tyrosine at codon 625 is replaced by cysteine, 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. |
Invitae | RCV000698245 | SCV000826900 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 625 of the MLH1 protein (p.Tyr625Cys). This variant is present in population databases (rs748851107, gnomAD 0.0009%). 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: 232394). 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 with a positive predictive value of 95%. 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. |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001255521 | SCV001431961 | uncertain significance | not specified | 2020-08-24 | criteria provided, single submitter | clinical testing | Variant summary: MLH1 c.1874A>G (p.Tyr625Cys) results in a non-conservative amino acid change located in the C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251408 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1874A>G in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Both laboratories cited the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
Color Diagnostics, |
RCV000223006 | SCV001734522 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-02-06 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 625 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 MLH1-related disorders in the literature. This variant has been identified in 1/251408 chromosomes 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. |
Gene |
RCV001547023 | SCV001766642 | uncertain significance | not provided | 2020-01-10 | criteria provided, single submitter | clinical testing | Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge |
Baylor Genetics | RCV003462495 | SCV004195056 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-10-16 | criteria provided, single submitter | clinical testing | |
All of Us Research Program, |
RCV003997970 | SCV004843227 | uncertain significance | Lynch syndrome | 2023-03-28 | criteria provided, single submitter | clinical testing | This missense variant replaces tyrosine with cysteine at codon 625 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 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 been identified in 1/251408 chromosomes 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. |