ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.668C>G (p.Ala223Gly)

dbSNP: rs756045117
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000696943 SCV000825527 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-05-27 criteria provided, single submitter clinical testing 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function. ClinVar contains an entry for this variant (Variation ID: 574890). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 223 of the MLH1 protein (p.Ala223Gly).
Ambry Genetics RCV002360776 SCV002664863 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-19 criteria provided, single submitter clinical testing The p.A223G variant (also known as c.668C>G), located in coding exon 8 of the MLH1 gene, results from a C to G substitution at nucleotide position 668. The alanine at codon 223 is replaced by glycine, an amino acid with 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.
Baylor Genetics RCV003465598 SCV004190632 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-08-29 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004807099 SCV005427847 uncertain significance Lynch syndrome 2024-02-22 criteria provided, single submitter clinical testing This missense variant replaces alanine with glycine at codon 223 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 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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