ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.828A>G (p.Ile276Met)

gnomAD frequency: 0.00001  dbSNP: rs1036438114
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001058898 SCV001223496 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-12-26 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV001181965 SCV001347230 uncertain significance Hereditary cancer-predisposing syndrome 2019-11-26 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 276 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/31400 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.
Ambry Genetics RCV001181965 SCV002677243 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-10 criteria provided, single submitter clinical testing The p.I276M variant (also known as c.828A>G), located in coding exon 10 of the MLH1 gene, results from an A to G substitution at nucleotide position 828. The isoleucine at codon 276 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is well 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.
All of Us Research Program, National Institutes of Health RCV004000106 SCV004840912 uncertain significance Lynch syndrome 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 276 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/31400 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.
Baylor Genetics RCV004570234 SCV005057996 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2024-01-19 criteria provided, single submitter clinical testing

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