Submissions for variant NM_000249.4(MLH1):c.343A>G (p.Ile115Val)

gnomAD frequency: 0.00001  dbSNP: rs371667663

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000528097	SCV000625151	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-11-10	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 115 of the MLH1 protein (p.Ile115Val). This variant is present in population databases (rs371667663, gnomAD 0.003%). This missense change has been observed in individual(s) with clinical features of Lynch syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 455430). 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.
Ambry Genetics	RCV000566781	SCV000664792	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-15	criteria provided, single submitter	clinical testing	The p.I115V variant (also known as c.343A>G), located in coding exon 4 of the MLH1 gene, results from an A to G substitution at nucleotide position 343. The isoleucine at codon 115 is replaced by valine, an amino acid with highly similar properties. In one study, this variant was detected in 0/165 colorectal cancer and/or polyposis patients and was identified in 1/2512 control individuals from a healthy population database (Rosenthal EA et al. Hum Genet, 2018 Oct;137:795-806). This amino acid position is 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.
Color Diagnostics, LLC DBA Color Health	RCV000566781	SCV001348197	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-27	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with valine at codon 115 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 been reported in at least one individual with clinical features of Lynch Syndrome (ClinVar SCV000625151.7). This variant has been identified in 2/251412 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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798871	SCV002042077	uncertain significance	Breast and/or ovarian cancer	2023-04-05	criteria provided, single submitter	clinical testing
GeneDx	RCV002260645	SCV002540398	uncertain significance	not provided	2022-06-26	criteria provided, single submitter	clinical testing	Not observed at a 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)