Submissions for variant NM_000249.4(MLH1):c.1744C>G (p.Leu582Val)

gnomAD frequency: 0.00001  dbSNP: rs63751713

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000627697	SCV000543553	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 582 of the MLH1 protein (p.Leu582Val). This variant is present in population databases (rs63751713, gnomAD 0.006%). This missense change has been observed in individual(s) with cancer and hereditary non-polyposis colorectal cancer (HNPCC) (PMID: 7757073, 31386297). ClinVar contains an entry for this variant (Variation ID: 89869). 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. Experimental studies have shown that this missense change does not substantially affect MLH1 function (PMID: 9697702, 10037723, 12810663, 15864295, 17510385). 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.
Ambry Genetics	RCV000571505	SCV000662046	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-16	criteria provided, single submitter	clinical testing	The p.L582V variant (also known as c.1744C>G), located in coding exon 16 of the MLH1 gene, results from a C to G substitution at nucleotide position 1744. The leucine at codon 582 is replaced by valine, an amino acid with highly similar properties. This variant was identified in an individual meeting Amsterdam II criteria and the mismatch repair (MMR) activity for the variant was either gone or reduced in a functional assay using yeast (Shimodaira H et al. Nat. Genet. 1998 Aug;19(4):384-9). However, several studies have demonstrated expression levels, PMS2 binding, and MMR activity were similar to that of wild type MLH1 (Guerrette S et al., J. Biol. Chem. 1999 Mar; 274(10):6336-41; Kondo E et al., Cancer Res. 2003 Jun; 63(12):3302-8;Takahashi M et al., Cancer Res. 2007 May; 67(10):4595-604; Vo AT et al., EMBO Rep. 2005 May; 6(5):438-44). This variant has been identified in 45/12503 unselected Japanese colorectal cancer patients and in 102/23705 controls. (Fujita M et al. Clin Gastroenterol Hepatol, 2022 Sep;20:2132-2141.e9). 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	RCV000571505	SCV000908644	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-08	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 582 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). Functional studies have shown that this variant retained 93% of wild type MLH1 mismatch repair activity via yeast-2-hybrid and mismatch repair activity assays (PMID: 17510385, 15864295, 12810663, 10037723, 9697702, 21064154). Other functional studies reported altered protein interaction with mismatch repair machinery and loss of dominant mutator effect via yeast-2-hybrid and dominant mutator assays (PMID: 9697702, 15864295). This variant has been reported in individuals affected with Lynch syndrome, colorectal cancer, gastric cancer and mesothelioma (PMID: 7757073, 9697702, 17510385, 29050249, 29192238, 32206572, 33309985). This variant has been identified in 1/246040 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and has been observed in over one hundred individuals from a healthy control population (PMID: 33309985). 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.
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030630	SCV001193612	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193957	SCV001363153	uncertain significance	not specified	2023-12-11	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1744C>G (p.Leu582Val) results in a 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 benign effect of the variant on protein function. The variant was absent in 251262 control chromosomes (gnomAD) but was reported at a frequency of 0.001409 from 108604 chromosomes in ToMMo 54KJPN (jMorp variation ID0191aa67588b00000). c.1744C>G has been reported in the literature in at-least one family with Lynch Syndrome (Han_1995), individuals affected with various types of cancer (example: Kiyozumi_2019, Fuijita_2022,Okawa_2023) as well as in individuals from control study cohorts (example: Fuijita_2022, and Okawa_2023). Several publications report experimental evidence evaluating an impact on protein function. These results reproducibly reported no damaging effect of this variant on measures of interaction with PMS2, in-vitro MMR activity, and interaction with hMRE11 (Guerrette_1999, Takahashi_2007, Vo_2005, Kondo_2003). The following publications have been ascertained in the context of this evaluation (PMID: 10037723, 7757073, 12810663, 17510385, 15864295, 31386297, 26332594, 33309985, 36243179). Four submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997117	SCV004843205	uncertain significance	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 582 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. A different variant affecting the same codon, c.1745T>C (p.Leu582Pro), is considered to be disease-causing (ClinVar variation ID: 89871), suggesting that leucine or similar amino acid at this position is important for the protein function. Functional studies have reported this variant to be normal to partially abnormal in mismatch repair and associated activities (PMID: 9697702, 17510385). Similarly, there was reported reduced PMS2 binding by co-immunoprecipitation (PMID: 20978114) but near wild-type PMS2 binding by yeast two-hybrid and GST pull down assays (PMID: 12810663, 15864295, 10037723). This variant has been reported in at least two families affected with Lynch syndrome associated cancer and the variant is reported to segregate with disease (PMID: 7757073, 9697702, 17510385, InSiGHT database). This variant has been identified in 1/246040 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.
Myriad Genetics, Inc.	RCV004019101	SCV004930993	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2024-01-22	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726].