Submissions for variant NM_000249.4(MLH1):c.779T>A (p.Leu260His)

dbSNP: rs63751283

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000463982	SCV000543628	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with histidine, which is basic and polar, at codon 260 of the MLH1 protein (p.Leu260His). 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: 405420). 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 expected to disrupt MLH1 protein function with a positive predictive value of 95%. This variant disrupts the p.Leu260 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10882759, 22290698, 24362816, 27629256, 28874130). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx	RCV000484437	SCV000567372	uncertain significance	not provided	2015-07-17	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.779T>A at the cDNA level, p.Leu260His (L260H) at the protein level, and results in the change of a Leucine to a Histidine (CTC>CAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Leu260His 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 Leucine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Leu260His occurs at a position that is conserved across species and is not located in a known functional domain (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 Leu260His is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000561786	SCV000662090	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-13	criteria provided, single submitter	clinical testing	The p.L260H variant (also known as c.779T>A), located in coding exon 9 of the MLH1 gene, results from a T to A substitution at nucleotide position 779. The leucine at codon 260 is replaced by histidine, an amino acid with 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.
Counsyl	RCV000662376	SCV000784771	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-12-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662376	SCV004020283	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-10	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
All of Us Research Program, National Institutes of Health	RCV004000658	SCV004825576	uncertain significance	Lynch syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with histidine at codon 260 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. A different variant affecting the same codon, c.779T>G (p.Leu260Arg), is considered to be disease-causing (ClinVar variation ID: 90350), suggesting that this position may be important for the protein function. 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.