Submissions for variant NM_000249.4(MLH1):c.9C>G (p.Phe3Leu)

gnomAD frequency: 0.00004  dbSNP: rs779759678

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165278	SCV000215995	likely benign	Hereditary cancer-predisposing syndrome	2018-05-02	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV000459216	SCV000543576	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3 of the MLH1 protein (p.Phe3Leu). This variant is present in population databases (rs779759678, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 185790). 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 with a negative predictive value of 95%. 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	RCV000483373	SCV000567950	uncertain significance	not provided	2022-03-17	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; In-silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Not observed in any pancreatic cancer cases but was observed in an unaffected control (Mizukami 2020); This variant is associated with the following publications: (PMID: 22753075, 32980694)
Color Diagnostics, LLC DBA Color Health	RCV000165278	SCV000911474	likely benign	Hereditary cancer-predisposing syndrome	2017-08-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001193240	SCV001361967	uncertain significance	not specified	2019-11-15	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.9C>G (p.Phe3Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251472 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.9C>G in individuals affected with Hereditary Non-Polyposis Colon Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as likely benign (n=2) and as uncertain significance (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Genetic Services Laboratory, University of Chicago	RCV001193240	SCV002071810	uncertain significance	not specified	2021-08-16	criteria provided, single submitter	clinical testing	DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.9C>G, in exon 1 that results in an amino acid change, p.Phe3Leu. This sequence change has been described in the gnomAD database with frequency of 0.0023% in the non-Finnish European subpopulation (dbSNP rs779759678). The p.Phe3Leu change affects a poorly conserved amino acid residue located in a domain of the MLH1 protein that is not known to be functional. The p.Phe3Leu substitution appears to be benign using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). This sequence change does not appear to have been previously described in individuals with MLH1-related disorders. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Phe3Leu change remains unknown at this time.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291579	SCV002584604	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2022-07-05	criteria provided, single submitter	clinical testing	The MLH1 c.9C>G (p.Phe3Leu) missense change has a maximum subpopulation frequency of 0.0023% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org). The in silico tool REVEL is inconclusive about a pathogenic or benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with Lynch syndrome or constitutional mismatch repair deficiency syndrome. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000483373	SCV004220909	uncertain significance	not provided	2023-02-23	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000023 (3/129188 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an unaffected individual in a large pancreatic cancer study (PMID: 32980694 (2020)). In addition, in a large breast cancer study, the variant was reported in an individual with breast cancer as well as in an unaffected individual (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/MLH1). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003995409	SCV004835209	likely benign	Lynch syndrome	2023-10-06	criteria provided, single submitter	clinical testing