Submissions for variant NM_000249.4(MLH1):c.1901G>T (p.Gly634Val)

gnomAD frequency: 0.00001  dbSNP: rs786202396

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165186	SCV000215898	uncertain significance	Hereditary cancer-predisposing syndrome	2023-10-31	criteria provided, single submitter	clinical testing	The p.G634V variant (also known as c.1901G>T), located in coding exon 17 of the MLH1 gene, results from a G to T substitution at nucleotide position 1901. The glycine at codon 634 is replaced by valine, an amino acid with dissimilar properties. This amino acid position is highly 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.
Invitae	RCV000554358	SCV000625108	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 634 of the MLH1 protein (p.Gly634Val). This variant is present in population databases (rs786202396, gnomAD 0.007%). 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: 185711). 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 expected to disrupt 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.
GeneDx	RCV001575774	SCV001802833	uncertain significance	not provided	2023-05-31	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; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12799449, 20533529, 22753075)
All of Us Research Program, National Institutes of Health	RCV003995399	SCV004843233	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with valine at codon 634 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 MLH1-related disorders in the literature. This variant has been identified in 1/31390 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.