Submissions for variant NM_000249.4(MLH1):c.2017T>C (p.Phe673Leu)

gnomAD frequency: 0.00001  dbSNP: rs587780680

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000122972	SCV000166247	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 673 of the MLH1 protein (p.Phe673Leu). 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: 135848). 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. 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	RCV000215155	SCV000273395	uncertain significance	Hereditary cancer-predisposing syndrome	2021-03-23	criteria provided, single submitter	clinical testing	The p.F673L variant (also known as c.2017T>C), located in coding exon 18 of the MLH1 gene, results from a T to C substitution at nucleotide position 2017. The phenylalanine at codon 673 is replaced by leucine, an amino acid with highly similar properties. 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.
GeneDx	RCV000479272	SCV000572480	uncertain significance	not provided	2016-12-15	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.2017T>C at the cDNA level, p.Phe673Leu (F673L) at the protein level, and results in the change of a Phenylalanine to a Leucine (TTT>CTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Phe673Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Leucine share similar properties, this is considered a conservative amino acid substitution. MLH1 Phe673Leu occurs at a position that is conserved across species and is located in the region of interaction with PMS2, MLH3, and PMS1 (Pang 1997, Raevaara 2005, Hardt 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MLH1 Phe673Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000215155	SCV001356445	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 673 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 not been reported in individuals affected with MLH1-related disorders in the literature. 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.
Baylor Genetics	RCV003460869	SCV004195054	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-16	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997401	SCV004843252	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 673 of the MLH1 protein. Computational prediction tool suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >=0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. 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.