Submissions for variant NM_000249.4(MLH1):c.266A>G (p.Glu89Gly)

gnomAD frequency: 0.00001  dbSNP: rs758110228

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000689236	SCV000816877	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-23	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 89 of the MLH1 protein (p.Glu89Gly). This variant is present in population databases (rs758110228, gnomAD 0.003%). 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: 568777). 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 not 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.
Ambry Genetics	RCV001016259	SCV001177195	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	The p.E89G variant (also known as c.266A>G), located in coding exon 3 of the MLH1 gene, results from an A to G substitution at nucleotide position 266. The glutamic acid at codon 89 is replaced by glycine, an amino acid with similar properties. This alteration has been observed in an individual whose colorectal tumor demonstrated loss of MLH1 and PMS2 expression on immunohistochemistry (IHC) (Ambry internal data). Based on internal structural analysis using published crystal structures, E89G has a low destabilization energy and the non-interfacial residue is expected to be tolerated (Ban C et al. Cell, 1999 Apr;97:85-97; Wu H et al. Acta Crystallogr F Struct Biol Commun, 2015 Aug;71:981-5). 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.
Color Diagnostics, LLC DBA Color Health	RCV001016259	SCV001735151	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 89 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 by an external laboratory in an individual affected with colorectal cancer whose tumor displayed loss of MLH1 and PMS2 protein expression via immunohistochemistry analysis (ClinVar SCV001177195.3). This variant has been identified in 2/251402 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.
All of Us Research Program, National Institutes of Health	RCV004004296	SCV004835263	uncertain significance	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with glycine at codon 89 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 by an external laboratory in an individual affected with colorectal cancer whose tumor displayed loss of MLH1 and PMS2 protein expression via immunohistochemistry analysis (ClinVar SCV001177195.3). This variant has been identified in 2/251402 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.