Submissions for variant NM_000249.4(MLH1):c.1590C>G (p.Phe530Leu)

dbSNP: rs752241564

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484164	SCV000565812	uncertain significance	not provided	2015-03-04	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1590C>G at the cDNA level, p.Phe530Leu (F530L) at the protein level, and results in the change of a Phenylalanine to a Leucine (VOUS). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Phe530Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating 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 Phe530Leu occurs at a position that is conserved across species and is located within the region of interaction with PMS2/MLH3/PMS1 (Raevaara 2005) and within the region of interaction with EXO1 (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MLH1 Phe530Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000630164	SCV000751120	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-07-08	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 530 of the MLH1 protein (p.Phe530Leu). This variant is present in population databases (rs752241564, gnomAD 0.0009%). 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: 418617). 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	RCV002402381	SCV002708375	uncertain significance	Hereditary cancer-predisposing syndrome	2019-06-24	criteria provided, single submitter	clinical testing	The p.F530L variant (also known as c.1590C>G), located in coding exon 14 of the MLH1 gene, results from a C to G substitution at nucleotide position 1590. The phenylalanine at codon 530 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004002261	SCV004843178	uncertain significance	Lynch syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This missense variant replaces phenylalanine with leucine at codon 530 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). 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 been identified in 1/251236 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.