ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1150G>A (p.Val384Ile)

gnomAD frequency: 0.00001  dbSNP: rs757350157
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000470621 SCV000543629 benign Hereditary nonpolyposis colorectal neoplasms 2025-01-02 criteria provided, single submitter clinical testing
Ambry Genetics RCV002348276 SCV002621453 uncertain significance Hereditary cancer-predisposing syndrome 2024-04-28 criteria provided, single submitter clinical testing The p.V384I variant (also known as c.1150G>A), located in coding exon 12 of the MLH1 gene, results from a G to A substitution at nucleotide position 1150. The valine at codon 384 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Johns Hopkins Genomics, Johns Hopkins University RCV003150815 SCV003839109 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2022-12-14 criteria provided, single submitter clinical testing This MLH1 missense variant (rs757350157) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 1/151552 total alleles; 0.00066%; no homozygotes). It has been reported in ClinVar (Variation ID 405421), but has not been reported in the literature, to our knowledge. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated, and the valine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.1150G>A; p.Val384Ile in MLH1 to be uncertain at this time.
Johns Hopkins Genomics, Johns Hopkins University RCV003150814 SCV003839110 uncertain significance Mismatch repair cancer syndrome 1 2022-12-14 criteria provided, single submitter clinical testing This MLH1 missense variant (rs757350157) is rare (<0.1%) in a large population dataset (gnomAD v3.1.2: 1/151552 total alleles; 0.00066%; no homozygotes). It has been reported in ClinVar (Variation ID 405421), but has not been reported in the literature, to our knowledge. Of two bioinformatics tools queried, one predicts that the substitution would be damaging, while the other predicts that it would be tolerated, and the valine residue at this position is evolutionarily conserved across all of the species assessed. We consider the clinical significance of c.1150G>A; p.Val384Ile in MLH1 to be uncertain at this time.
All of Us Research Program, National Institutes of Health RCV004000659 SCV004826248 uncertain significance Lynch syndrome 2023-10-27 criteria provided, single submitter clinical testing
Baylor Genetics RCV003150815 SCV005057963 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2024-03-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV004999429 SCV005623544 uncertain significance not provided 2023-10-16 criteria provided, single submitter clinical testing The MLH1 c.1150G>A (p.Val384Ile) variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251430 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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