Submissions for variant NM_000249.4(MLH1):c.1165C>T (p.Arg389Trp)

gnomAD frequency: 0.00003  dbSNP: rs61751644

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165994	SCV000216752	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-16	criteria provided, single submitter	clinical testing	The p.R389W variant (also known as c.1165C>T), located in coding exon 12 of the MLH1 gene, results from a C to T substitution at nucleotide position 1165. The arginine at codon 389 is replaced by tryptophan, an amino acid with dissimilar properties. This variant was reported in two individuals ascertained from the Danish HNPCC register who both had a history of breast and a metachronous colon cancer; however, IHC staining of their breast tumors revealed intact MLH1/PMS2 proteins (Jensen UB et al. Breast Cancer Res. Treat. 2010 Apr; 120(3):777-82). In another study, a 60 year old male diagnosed with an MSI-High colon cancer, also had this variant; however, he had no first degree relatives with cancer (Samowitz WS et al. Gastroenterology. 2001 Oct; 121(4):830-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075132	SCV000266176	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000627719	SCV000543540	benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV001563149	SCV001786038	uncertain significance	not provided	2023-09-22	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; Published functional studies demonstrate normal cellular localization, EXO1 and PMS2 binding, and in vitro mismatch repair activity (Andersen 2012); Observed in individuals with a personal and/or family history of colorectal, breast, and other cancers (Samowitz 2001, Nilbert 2009, Jensen 2010, Shirts 2016); This variant is associated with the following publications: (PMID: 19698169, 19575290, 11606497, 18566915, 22753075, 20020535, 15849733, 26845104, 22883484, 29106415, 28642281, 31784484)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV003444197	SCV004171451	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-22	criteria provided, single submitter	clinical testing	The MLH1 c.1165C>T (p.Arg389Trp) missense change has a maximum subpopulation frequency of 0.004% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in individuals with colon cancer (PMID: 11606497, 19575290). In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Baylor Genetics	RCV003444197	SCV004190630	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165994	SCV004359218	uncertain significance	Hereditary cancer-predisposing syndrome	2023-05-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 389 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). A functional study reported the variant had normal protein localization and binding to PMS2 and EXO1 (PMID: 22753075). This variant has been reported in individuals affected with Lynch syndrome (PMID: 19575290) or colorectal cancer (PMID: 11606497). This variant has been identified in 1/246180 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.
All of Us Research Program, National Institutes of Health	RCV000075132	SCV004840966	uncertain significance	Lynch syndrome	2024-08-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with tryptophan at codon 389 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). A functional study reported the variant had normal protein localization and binding to PMS2 and EXO1, but may be impaired for mismatch repair (PMID: 22753075). This variant has been reported in individuals affected with Lynch syndrome (PMID: 19575290) or colorectal cancer (PMID: 11606497). This variant has been identified in 1/246180 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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000582826	SCV000691861	uncertain significance	not specified		no assertion criteria provided	clinical testing