Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000221562 | SCV000275455 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-09-30 | criteria provided, single submitter | clinical testing | The p.E37Q variant (also known as c.109G>C), located in coding exon 1 of the MLH1 gene, results from a G to C substitution at nucleotide position 109. The glutamic acid at codon 37 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in an individual whose family history met Amsterdam criteria for Lynch syndrome and whose colon tumor displayed high microsatellite instability (MSI-H), but had normal MMR gene protein expression by immunohistochemistry (IHC) (Ambry internal data). This alteration was also identified in the germline of an individual who had a family history of Lynch-associated cancers and a MSI-H endometrial tumor with MLH1 copy-neutral loss of heterozygosity (CN-LOH), but normal IHC (Ambry internal data). In a cohort of Indian patients with colorectal cancer meeting Bethesda criteria, this alteration was reported in cis with an MLH1 frameshift mutation in an individual whose tumor demonstrated microsatellite instability and loss of MLH1 and PMS2 protein expression (Bashyam MD et al. Mol Carcinog. 2014 Nov 24). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. |
| Invitae | RCV000555996 | SCV000625040 | uncertain significance | Hereditary nonpolyposis colorectal neoplasms | 2017-07-09 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in an individual affected with Lynch syndrome (PMID: 25420488). However, in that individual a truncating variant was also identified in cis in MLH1, and the impact of this c.109G>C variant is not known. ClinVar contains an entry for this variant (Variation ID: 231565). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glutamic acid with glutamine at codon 37 of the MLH1 protein (p.Glu37Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. |
| University of Washington Department of Laboratory Medicine, |
RCV000664318 | SCV000788254 | likely pathogenic | Lynch syndrome | 2018-02-07 | criteria provided, single submitter | clinical testing | The MLH1 p.E37K variant has been identified in an individual with a family history that meets current Amerstam criteria for Lynch syndrome. Testing performed on tumor tissue of a paitient with germline MLH1 p.E37K supports that this variant is likely pathogenic. Specifically, the germline MLH1 variant was detecting with loss of heterozygosity (LOH) of the second allele in the patient's tumor. Tumor screening showed the tissue was MSI-High with intact MLH1 protein expression by IHC. A different variant at the same codon of MLH1 (p.E37) has been observed as a double somatic mutation in a tumor tissue of a patient with endometrial adenocarcinoma that was microsatellite instability high, with intact MLH1 protein expression by IHC, and negative germline testing (UWMC internal data). This information suggests that mutations at codon 37 of the MLH1 protein may cause loss of protein function while leaving MLH1 protein staining intact on IHC. This variant has also been previously reported in a group of patients meeting Bethesda criteria, but occured in cis with a separate MLH1 frameshift mutation (PMID 25420488). This variant is not currently reported in population databases and occurs at a amino acid position that is conserved across species. |
| Molekularpathologisches Zentrum, |
RCV001808580 | SCV002058107 | likely pathogenic | Lung cancer | 2022-01-13 | no assertion criteria provided | research |