Submissions for variant NM_000249.4(MLH1):c.2151A>T (p.Glu717Asp)

gnomAD frequency: 0.00001  dbSNP: rs1553665630

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000576091	SCV000676313	uncertain significance	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	clinical testing	The p.E717D variant (also known as c.2151A>T), located in coding exon 19 of the MLH1 gene, results from an A to T substitution at nucleotide position 2151. The glutamic acid at codon 717 is replaced by aspartic acid, an amino acid with highly similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with T-cell ALL (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). 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.
Invitae	RCV000630032	SCV000750988	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-25	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. This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 717 of the MLH1 protein (p.Glu717Asp). This variant is not present in population databases (gnomAD no frequency). 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: 487010). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function.
GeneDx	RCV001557751	SCV001779568	uncertain significance	not provided	2023-06-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Identified as a germline variant in a pediatric patient with leukemia (Zhang et al., 2015); This variant is associated with the following publications: (PMID: 12799449, 20533529, 22753075, 26580448)
All of Us Research Program, National Institutes of Health	RCV004001206	SCV004843286	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 717 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 individuals affected with T-cell acute lymphocytic leukemia (PMID: 26580448). 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.