Submissions for variant NM_000249.4(MLH1):c.2051A>C (p.Tyr684Ser)

dbSNP: rs267607886

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000485347	SCV000566010	uncertain significance	not provided	2015-03-24	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.2051A>C at the cDNA level, p.Tyr684Ser (Y684S) at the protein level, and results in the change of a Tyrosine to a Serine (TAT>TCT). MLH1 Tyr684Ser has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Tyr684Ser 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 Tyrosine and Serine differ in some properties, this is considered a semi-conservative amino acid substitution. MLH1 Tyr684Ser occurs at a position that is conserved across species and is located within the region of interaction with PMS2, MLH3,and PMS1 (Raevaara 2005). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MLH1 Tyr684Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000573920	SCV000669559	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-26	criteria provided, single submitter	clinical testing	The p.Y684S variant (also known as c.2051A>C), located in coding exon 18 of the MLH1 gene, results from an A to C substitution at nucleotide position 2051. The tyrosine at codon 684 is replaced by serine, an amino acid with dissimilar 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.
Color Diagnostics, LLC DBA Color Health	RCV000573920	SCV000689856	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-27	criteria provided, single submitter	clinical testing	This missense variant replaces Tyrosine with Serine at codon 684 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 been identified in 3/282622 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001044170	SCV001207951	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-04-08	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with serine, which is neutral and polar, at codon 684 of the MLH1 protein (p.Tyr684Ser). This variant is present in population databases (no rsID available, gnomAD 0.002%). 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: 418728). 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%. 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.
Sema4, Sema4	RCV000573920	SCV002528709	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-15	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004002267	SCV004843259	uncertain significance	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces Tyrosine with Serine at codon 684 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 been identified in 3/282622 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.
Baylor Genetics	RCV004568151	SCV005057986	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-02-09	criteria provided, single submitter	clinical testing