ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1223C>A (p.Pro408His)

dbSNP: rs1241839317
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000819990 SCV000960682 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2022-05-21 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with histidine, which is basic and polar, at codon 408 of the MLH1 protein (p.Pro408His). 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. ClinVar contains an entry for this variant (Variation ID: 662368). 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. 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.
Ambry Genetics RCV001010410 SCV001170609 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-02 criteria provided, single submitter clinical testing The p.P408H variant (also known as c.1223C>A), located in coding exon 12 of the MLH1 gene, results from a C to A substitution at nucleotide position 1223. The proline at codon 408 is replaced by histidine, an amino acid with 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.
Baylor Genetics RCV003467495 SCV004192988 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-06-09 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002818 SCV004840978 uncertain significance Lynch syndrome 2023-05-16 criteria provided, single submitter clinical testing This missense variant replaces proline with histidine at codon 408 of the MLH1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, 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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