Submissions for variant NM_000249.4(MLH1):c.5C>T (p.Ser2Leu)

gnomAD frequency: 0.00001  dbSNP: rs587779029

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160548	SCV000211126	uncertain significance	not provided	2020-09-21	criteria provided, single submitter	clinical testing	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: 20176655)
Ambry Genetics	RCV000221241	SCV000274230	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-14	criteria provided, single submitter	clinical testing	The p.S2L variant (also known as c.5C>T), located in coding exon 1 of the MLH1 gene, results from a C to T substitution at nucleotide position 5. The serine at codon 2 is replaced by leucine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000555345	SCV000625180	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 2 of the MLH1 protein (p.Ser2Leu). This variant is present in population databases (rs587779029, gnomAD 0.01%). This missense change has been observed in individual(s) with breast cancer, squamous cell carcinoma, and/or unspecified cancer (PMID: 34326862, 34598035, 35264596). ClinVar contains an entry for this variant (Variation ID: 182533). 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.
Color Diagnostics, LLC DBA Color Health	RCV000221241	SCV000684852	uncertain significance	Hereditary cancer-predisposing syndrome	2022-12-21	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 2 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). 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 7/251478 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.
Mendelics	RCV000708910	SCV000837990	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000160548	SCV000889400	uncertain significance	not provided	2017-09-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001147827	SCV001308678	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002229427	SCV002511437	uncertain significance	not specified	2022-12-12	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.5C>T (p.Ser2Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251478 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.5C>T has been reported in the literature as a VUS in settings of multigene panel testing in an individual affected with endometrial cancer with no family history of cancer and in an individual suspected of Hereditary Nonpolyposis Colorectal Cancer (HNPCC)/Lynch Syndrome who met revised Bethesda guidelines (e.g. Kim_2022, Park_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV001147827	SCV004190626	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-08-31	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000708910	SCV004835208	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with leucine at codon 2 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). 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 7/251478 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.