Submissions for variant NM_000249.4(MLH1):c.827T>C (p.Ile276Thr)

dbSNP: rs1253275403

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000522950	SCV000618262	uncertain significance	not provided	2024-12-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 32658311, 22753075, 38940262)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000707270	SCV000836360	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-10-29	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 276 of the MLH1 protein (p.Ile276Thr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). 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: 449833). Invitae Evidence Modeling incorporating data from in vitro experimental studies (internal data) indicates that this missense variant is not expected to disrupt MLH1 function with a negative predictive value of 95%. RNA analysis performed to evaluate the impact of this missense change on mRNA splicing indicates it does not significantly alter splicing (internal data). 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	RCV001027361	SCV001189903	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-29	criteria provided, single submitter	clinical testing	The p.I276T variant (also known as c.827T>C), located in coding exon 10 of the MLH1 gene, results from a T to C substitution at nucleotide position 827. The isoleucine at codon 276 is replaced by threonine, an amino acid with similar properties. This alteration was seen in 1/732 breast cancer patients, 0/189 colorectal cancer patients and 0/490 cancer-free elderly controls in a Turkish population (Akcay IM et al. Int J Cancer, 2021 Jan;148:285-295). This amino acid position is well 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	RCV001027361	SCV001736230	uncertain significance	Hereditary cancer-predisposing syndrome	2022-07-26	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 276 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. A different missense variant, p.Ile276Arg, at this codon has been reported as disease-causing in ClinVar by InSiGHT (ClinVar variation ID: 520540). This variant has been identified in 1/251476 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.
All of Us Research Program, National Institutes of Health	RCV004003606	SCV004840911	uncertain significance	Lynch syndrome	2023-05-31	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with threonine at codon 276 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. A different missense variant, p.Ile276Arg, at this codon has been reported as disease-causing in ClinVar by InSiGHT (ClinVar variation ID: 520540). This variant has been identified in 1/251476 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.