Submissions for variant NM_000249.4(MLH1):c.217C>G (p.Leu73Val)

dbSNP: rs766608278

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000572070	SCV000676321	uncertain significance	Hereditary cancer-predisposing syndrome	2021-08-26	criteria provided, single submitter	clinical testing	The p.L73V variant (also known as c.217C>G), located in coding exon 3 of the MLH1 gene, results from a C to G substitution at nucleotide position 217. The leucine at codon 73 is replaced by valine, an amino acid with highly similar properties. This alteration was identified in a cohort of individuals with advanced cancer that were tested using a targeted tumor-normal sequencing panel (Mandelker D et al. JAMA, 2017 09;318:825-835). 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	RCV000572070	SCV000908601	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-04	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 73 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 1/251326 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.
Invitae	RCV001048140	SCV001212130	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-10-20	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is present in population databases (rs766608278, gnomAD 0.0009%). This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 73 of the MLH1 protein (p.Leu73Val). ClinVar contains an entry for this variant (Variation ID: 487017). 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function.
Sema4, Sema4	RCV000572070	SCV002528727	uncertain significance	Hereditary cancer-predisposing syndrome	2022-01-26	criteria provided, single submitter	curation
GeneDx	RCV002469209	SCV002765521	uncertain significance	not provided	2022-12-13	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; Observed in an individual with advanced cancer undergoing multi-gene panel testing (Mandelker et al., 2017); This variant is associated with the following publications: (PMID: 22753075, 28873162)
All of Us Research Program, National Institutes of Health	RCV004001207	SCV004835255	uncertain significance	Lynch syndrome	2023-08-15	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 73 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). A function study using a human-yeast hybrid DNA mismatch repair assay found this variant resulted in a partial loss-of-function (PMID: 15475387). This variant has not been reported in individuals affected with hereditary cancer in the literature. However, a different missense at the same codon, p.Leu73Arg, has been reported in an individual affected with a biallelic case of constitutional DNA mismatch repair deficiency syndrome (PMID: 22692065). This variant has been identified in 1/251326 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.