ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1049C>G (p.Pro350Arg)

dbSNP: rs1575533938
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001017081 SCV001178107 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-23 criteria provided, single submitter clinical testing The p.P350R variant (also known as c.1049C>G), located in coding exon 12 of the MLH1 gene, results from a C to G substitution at nucleotide position 1049. The proline at codon 350 is replaced by arginine, 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001035711 SCV001199045 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-03-04 criteria provided, single submitter clinical testing ClinVar contains an entry for this variant (Variation ID: 822049). This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 350 of the MLH1 protein (p.Pro350Arg). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. 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. 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.
All of Us Research Program, National Institutes of Health RCV004004563 SCV004828011 uncertain significance Lynch syndrome 2023-08-28 criteria provided, single submitter clinical testing This missense variant replaces proline with arginine at codon 350 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 not been identified 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.

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