Submissions for variant NM_000249.4(MLH1):c.46G>C (p.Val16Leu)

dbSNP: rs776643257

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000554111	SCV000625168	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-04	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 16 of the MLH1 protein (p.Val16Leu). This variant is present in population databases (rs776643257, gnomAD 0.006%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 31386297). ClinVar contains an entry for this variant (Variation ID: 455439). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV000565039	SCV000662085	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-02	criteria provided, single submitter	clinical testing	The p.V16L variant (also known as c.46G>C), located in coding exon 1 of the MLH1 gene, results from a G to C substitution at nucleotide position 46. The valine at codon 16 is replaced by leucine, an amino acid with highly similar properties. This alteration was detected in patient with colon cancer at age 67 that was microsatellite stable with intact immunohistochemistry for the mismatch repair genes (Kiyozumi Y et al. Cancer Med, 2019 Sep;8:5534-5543). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Color Diagnostics, LLC DBA Color Health	RCV000565039	SCV000684833	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-24	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 16 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 been reported in individuals affected with mesothelioma (PMID: 32206572), pancreatic cancer (PMID: 32980694), or Lynch syndrome associated cancers (PMID: 31386297) This variant has been identified in 1/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in multiple healthy control individuals (PMID: 32980694). 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.
Genetic Services Laboratory, University of Chicago	RCV001821471	SCV002067802	uncertain significance	not specified	2019-11-13	criteria provided, single submitter	clinical testing
GeneDx	RCV003156248	SCV003845491	uncertain significance	not provided	2023-03-21	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; This variant is associated with the following publications: (PMID: 28706299, 32206572, 22753075, 31386297)
All of Us Research Program, National Institutes of Health	RCV004003722	SCV004835220	uncertain significance	Lynch syndrome	2023-03-28	criteria provided, single submitter	clinical testing	This missense variant replaces valine with leucine at codon 16 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 been reported in individuals affected with mesothelioma (PMID: 32206572), pancreatic cancer (PMID: 32980694), or Lynch syndrome associated cancers (PMID: 31386297) This variant has been identified in 1/251438 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in multiple healthy control individuals (PMID: 32980694). 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.