Submissions for variant NM_000249.4(MLH1):c.1783A>T (p.Ser595Cys)

dbSNP: rs876658763

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001061460	SCV001226204	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 595 of the MLH1 protein (p.Ser595Cys). 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: 856069). 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 80%. 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.
Color Diagnostics, LLC DBA Color Health	RCV001186277	SCV001352652	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-18	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 595 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.
Ambry Genetics	RCV001186277	SCV004055641	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-26	criteria provided, single submitter	clinical testing	The p.S595C variant (also known as c.1783A>T), located in coding exon 16 of the MLH1 gene, results from an A to T substitution at nucleotide position 1783. The serine at codon 595 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. 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	RCV003442187	SCV004167638	uncertain significance	not provided	2023-10-31	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; This variant is associated with the following publications: (PMID: 12799449, 20533529, 22753075, 36243179)
All of Us Research Program, National Institutes of Health	RCV004000120	SCV004843216	uncertain significance	Lynch syndrome	2023-06-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 595 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.