Submissions for variant NM_000249.4(MLH1):c.637G>T (p.Val213Leu)

dbSNP: rs2308317

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000627709	SCV000543572	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-09-01	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 90300). 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. 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 not expected to disrupt MLH1 protein function. This missense change has been observed in individual(s) with hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 16810763, 17074586). This variant is present in population databases (rs2308317, gnomAD 0.01%). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 213 of the MLH1 protein (p.Val213Leu).
Color Diagnostics, LLC DBA Color Health	RCV000774696	SCV000908610	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 213 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study demonstrated this variant has no impact on RNA or protein expression (PMID: 28494185). This variant has been reported in a family affected with Lynch syndrome (PMID: 16810763, 15613555). This variant has been identified in 2/251170 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.
Ambry Genetics	RCV000774696	SCV001187344	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-15	criteria provided, single submitter	clinical testing	The p.V213L variant (also known as c.637G>T), located in coding exon 8 of the MLH1 gene, results from a G to T substitution at nucleotide position 637. The valine at codon 213 is replaced by leucine, an amino acid with highly similar properties. This alteration has been reported in a Chinese HNPCC family; however, no additional clinical details of the family were outlined (Wang XL et al. World J. Gastroenterol. 2006 Jul;12(25):4074-7). Functional studies have shown that this alteration results in both protein expression and mRNA expression similar to that of wild-type MLH1 (Arora S et al. Cancer Biol. Ther. 2017 Jul;18(7):519-533). This alteration was also identified in 1 of 1009 patients amongst a cohort of Chinese patients with a personal history of pancreatic ductal adenocarcinoma (Yin L et al. JAMA Netw Open, 2022 Feb;5:e2148721). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this alteration remains unclear.
Baylor Genetics	RCV003460712	SCV004195079	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-03	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997135	SCV004840884	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 213 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study demonstrated this variant has no impact on RNA or protein expression (PMID: 28494185). This variant has been reported in a family affected with Lynch syndrome (PMID: 16810763, 15613555). This variant has been identified in 2/251170 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.