Submissions for variant NM_000249.4(MLH1):c.1690C>T (p.Leu564Phe)

dbSNP: rs786202693

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165630	SCV000216366	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-22	criteria provided, single submitter	clinical testing	The p.L564F variant (also known as c.1690C>T), located in coding exon 15 of the MLH1 gene, results from a C to T substitution at nucleotide position 1690. The leucine at codon 564 is replaced by phenylalanine, an amino acid with highly similar 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. Based on the available evidence, the clinical significance of this alteration remains unclear.
Invitae	RCV000229336	SCV000284026	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-05	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 564 of the MLH1 protein (p.Leu564Phe). This variant is present in population databases (rs786202693, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 186100). 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. 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.
GeneDx	RCV000478918	SCV000570244	uncertain significance	not provided	2022-11-09	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075, 12799449, 20533529)
Counsyl	RCV000662425	SCV000784876	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-01-24	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165630	SCV000911977	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-26	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 564 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with synchronous endometrial/ovarian carcinoma that demonstrated high microsatellite instability and loss of MLH1 and PMS2 proteins via immunohistochemistry analysis (PMID: 34519692). This variant has also been reported in an individual affected with breast cancer as well as an unspecified cancer (PMID: 25186627). This variant has been identified in 1/251140 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1691T>G (p.Leu564Arg), is considered to be disease-causing (ClinVar variation ID: 1778147), suggesting that this position is important for the protein function. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001800495	SCV002046987	uncertain significance	not specified	2021-04-29	criteria provided, single submitter	clinical testing
Mendelics	RCV001800495	SCV002518248	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165630	SCV002528667	uncertain significance	Hereditary cancer-predisposing syndrome	2021-07-20	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001800495	SCV002600483	uncertain significance	not specified	2022-10-13	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1690C>T (p.Leu564Phe) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251140 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1690C>T has been reported in the literature in individuals affected with Breast Cancer (Tung_2014) and Synchronous Endometrial/Ovarian Cancer (Carnevali_2022). In the individual with endometrial/ovarian cancer, tumor analysis showed loss of MLH1 and PMS2 expression and evidence for high microsatellite instability (Carnevali_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submitters have assessed the variant since 2014: all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000662425	SCV004018114	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	RCV000662425	SCV004195037	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-23	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003995440	SCV004843194	uncertain significance	Lynch syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with phenylalanine at codon 564 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with synchronous endometrial/ovarian carcinoma that demonstrated high microsatellite instability and loss of MLH1 and PMS2 proteins via immunohistochemistry analysis (PMID: 34519692). This variant has also been reported in an individual affected with breast cancer as well as an unspecified cancer (PMID: 25186627). This variant has been identified in 1/251140 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant affecting the same codon, c.1691T>G (p.Leu564Arg), is considered to be disease-causing (ClinVar variation ID: 1778147), suggesting that this position is important for the protein function. 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.