Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000005905 | SCV000948820 | uncertain significance | Colorectal cancer, hereditary nonpolyposis, type 7 | 2018-11-16 | criteria provided, single submitter | clinical testing | This sequence change replaces tryptophan with arginine at codon 1276 of the MLH3 protein (p.Trp1276Arg). The tryptophan residue is weakly conserved and there is a moderate physicochemical difference between tryptophan and arginine. This variant is present in population databases (rs121908439, ExAC 0.03%). 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. This variant has been reported not to substantially affect MLH3 protein function (PMID: 18521850). This variant has been observed in individuals affected with colorectal cancers (PMID: 12702580, 16981255). ClinVar contains an entry for this variant (Variation ID: 5564). |
| Ambry Genetics | RCV004018571 | SCV002623791 | uncertain significance | not specified | 2024-03-12 | criteria provided, single submitter | clinical testing | The p.W1276R variant (also known as c.3826T>C), located in coding exon 7 of the MLH3 gene, results from a T to C substitution at nucleotide position 3826. The tryptophan at codon 1276 is replaced by arginine, an amino acid with dissimilar properties. This variant segregated with disease in one family with colorectal cancer meeting Amsterdam criteria II; however, it co-occurred with a paternally inherited MSH2 missense variant in all four affected siblings whose tumors were microsatellite stable and demonstrated normal MSH2 protein expression on immunohistochemistry (Liu HX et al. Cancer Res., 2003 Apr;63:1894-9; Lagerstedt Robinson K et al. J. Natl Cancer Inst., 2007 Feb;99:291-9). This alteration did not segregate with disease in one Chinese family with familial esophageal cancer (Liu HX et al. World J. Gastroenterol., 2006 Sep;12:5281-6). In one study, the W1276R variant as part of the MutLγ complex showed normal protein stability and interaction with MLH1 as compared to wild type MLH3; mismatch repair efficiency of the W1276R recombinant protein was also similar to that of wild type MutLγ in vitro (Korhonen MK et al, 2008 Sep;47:803-9). This amino acid position is not well conserved in available vertebrate species, and arginine is the reference amino acid in other 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. |
| OMIM | RCV000005905 | SCV000026087 | pathogenic | Colorectal cancer, hereditary nonpolyposis, type 7 | 2006-09-07 | no assertion criteria provided | literature only |