Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001296249 | SCV001485207 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2020-08-15 | criteria provided, single submitter | clinical testing | This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 18566915). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with arginine at codon 147 of the MLH1 protein (p.Gly147Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. 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. 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. |
| Color Diagnostics, |
RCV001804821 | SCV002052456 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-07-27 | criteria provided, single submitter | clinical testing | This missense variant replaces glycine with arginine at codon 147 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 been reported in findividuals suspected of having Lynch syndrome (PMID: 18566915). 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 | RCV001804821 | SCV002629095 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-07 | criteria provided, single submitter | clinical testing | The p.G147R variant (also known as c.439G>C), located in coding exon 5 of the MLH1 gene, results from a G to C substitution at nucleotide position 439. The glycine at codon 147 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been detected in the germline of a Danish colorectal cancer patient (Nilbert M et al. Fam Cancer. 2009;8(1):75-83). It has also been reported as somatic in an early-onset colorectal cancer patient whose tumor demonstrated microsatellite instability, loss of MLH1 and PMS2 protein expression on immunohistochemistry (IHC), and loss of heterozygosity (Pearlman R et al. JAMA Oncol. 2017 Apr 1;3(4):464-471). This alteration has also been detected in the germline of an individual whose colon tumor demonstrated loss of both MLH1/PMS2 protein expression on IHC and loss of heterozygosity (Ambry internal data). Based on an internal structural assessment, this alteration destabilizes the local environment in the ATPase domain (Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be deleterious and pathogenic by MAPP-MMR and PON-MMR in silico analyses, respectively (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60; Ali H et al. Hum Mutat. 2012 Apr;33(4):642-50). Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Baylor Genetics | RCV003460711 | SCV004190621 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 2 | 2023-09-04 | criteria provided, single submitter | clinical testing |