Submissions for variant NM_000249.4(MLH1):c.1487C>T (p.Pro496Leu)

gnomAD frequency: 0.00003  dbSNP: rs63750226

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164380	SCV000215015	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-10	criteria provided, single submitter	clinical testing	The p.P496L variant (also known as c.1487C>T), located in coding exon 13 of the MLH1 gene, results from a C to T substitution at nucleotide position 1487. The proline at codon 496 is replaced by leucine, an amino acid with similar properties. In a yeast-based functional analysis, this variant was associated with intact MLH1 expression, decreased/partial MMR activity, and a dominant mutator effect (Takahashi M et al. Cancer Res. 2007 May; 67(10):4595-604). 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000455152	SCV000539648	uncertain significance	not specified	2016-06-23	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Reported as somatic mutation in 1 tumor, 1 functional study show 65% MMR activity; ClinVar: 1 VUS
Invitae	RCV000473679	SCV000543555	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 496 of the MLH1 protein (p.Pro496Leu). This variant is present in population databases (rs63750226, gnomAD 0.007%). This missense change has been observed in individual(s) with MLH1-related conditions (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 185027). 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. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 17510385). 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.
Counsyl	RCV000662426	SCV000784877	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-01-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000164380	SCV001351183	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-06	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 496 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). A functional study has shown that this variant caused a partial reduction in mismatch repair activity, with the mutant protein retaining 65.7% of wild type activity (PMID: 17510385). To our knowledge, this variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31402 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.
GeneDx	RCV001529648	SCV001769910	uncertain significance	not provided	2021-03-09	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional assays demonstrate mismatch repair proficiency: 65% mismatch repair activity (Takahashi 2007); This variant is associated with the following publications: (PMID: 24362816, 17510385)
Sema4, Sema4	RCV000164380	SCV002528655	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-23	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000662426	SCV004018120	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	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.
Baylor Genetics	RCV000662426	SCV004195070	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-06	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995339	SCV004841023	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 496 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). A functional study has shown that this variant caused a partial reduction in mismatch repair activity, with the mutant protein retaining 65.7% of wild type activity (PMID: 17510385). To our knowledge, this variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has been identified in 1/31402 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529648	SCV001743452	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV001529648	SCV001924090	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001529648	SCV001958868	uncertain significance	not provided		no assertion criteria provided	clinical testing