Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV000791765 | SCV000931027 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2021-11-06 | criteria provided, single submitter | clinical testing | This missense change has been observed in individuals with clinical features of Lynch syndrome and/or bile duct cancer (PMID: 29345684; Invitae). It has also been observed to segregate with disease in related individuals. For these reasons, this variant has been classified as Pathogenic. This variant disrupts the c.1989G nucleotide in the MLH1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 10480359, 16395668, 18561205, 24278394). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on MLH1 function (PMID: 17510385). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C35"). ClinVar contains an entry for this variant (Variation ID: 639057). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 663 of the MLH1 protein (p.Glu663Asp). This variant also falls at the last nucleotide of exon 17, which is part of the consensus splice site for this exon. |
| Ambry Genetics | RCV002422677 | SCV002718540 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2020-07-06 | criteria provided, single submitter | clinical testing | The p.E663D variant (also known as c.1989G>C), located in coding exon 17 of the MLH1 gene, results from a G to C substitution at nucleotide position 1989. The glutamic acid at codon 663 is replaced by aspartic acid, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 17, which makes it likely to have some effect on normal mRNA splicing. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Another alteration at this position (c.1989G>T) was shown to cause an in-frame deletion of exon 17 based on several studies, and has been detected in multiple Lynch syndrome families (Wang Q et al. Hum. Genet. 1999 July;105:79-85; Auclair J et al. Hum. Mutat., 2006 Feb;27:145-54; De Lellis L et al. PLoS ONE, 2013 Nov;8:e81194; Magnani G et al. Gastroenterol Res Pract, 2015 Oct;2015:132190). MLH1 c.1989G>C was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| All of Us Research Program, |
RCV004001556 | SCV004843246 | likely pathogenic | Lynch syndrome | 2023-06-26 | criteria provided, single submitter | clinical testing | This missense variant replaces glutamic acid with aspartic acid at codon 663 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). Splice site prediction tools suggest that this variant may have a significant impact on RNA splicing. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colorectal cancer that exhibited loss of MLH1 and PMS2 proteins by immunohistochemistry analyses (PMID: 33259954), and an individual affected with bile duct cancer (PMID: 29345684). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). A different nucleotide change resulting in the same missense amino acid change, c.1989G>T (p.Glu663Asp), has been reported in multiple individuals and families affected with hereditary non-polyposis colorectal cancer (PMID: 10480359, 16395668, 17510385, 18561205, 24278394), and RNA studies have shown that this variant results in cryptic donor site activation and exon 17 skipping (PMID: 10480359, 16395668, 18561205). The c.1989G>T (p.Glu663Asp) variant is considered to be disease-causing (ClinVar variation ID: 89980). Based on the available evidence, this variant is classified as Likely Pathogenic. |