ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.3166C>T (p.Leu1056Phe)

gnomAD frequency: 0.00003  dbSNP: rs188074706
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000793538 SCV000932894 uncertain significance not provided 2025-01-30 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1056 of the MSH3 protein (p.Leu1056Phe). This variant is present in population databases (rs188074706, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 640499). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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 RCV001018891 SCV001180185 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-09 criteria provided, single submitter clinical testing The p.L1056F variant (also known as c.3166C>T), located in coding exon 23 of the MSH3 gene, results from a C to T substitution at nucleotide position 3166. The leucine at codon 1056 is replaced by phenylalanine, an amino acid with highly similar 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.
Sema4, Sema4 RCV001018891 SCV002536499 uncertain significance Hereditary cancer-predisposing syndrome 2021-08-10 criteria provided, single submitter curation
GeneDx RCV000793538 SCV002576245 uncertain significance not provided 2024-03-26 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Baylor Genetics RCV003461078 SCV004196978 uncertain significance Endometrial carcinoma 2024-03-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000793538 SCV004221096 uncertain significance not provided 2023-08-31 criteria provided, single submitter clinical testing This variant has not been reported in the published literature. The frequency of this variant in the general population, 0.00051 (18/35418 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 predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Fulgent Genetics, Fulgent Genetics RCV005036133 SCV005666220 uncertain significance Endometrial carcinoma; Familial adenomatous polyposis 4 2024-04-18 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003975322 SCV004790038 uncertain significance MSH3-related disorder 2024-02-02 no assertion criteria provided clinical testing The MSH3 c.3166C>T variant is predicted to result in the amino acid substitution p.Leu1056Phe. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.051% of alleles in individuals of Latino descent in gnomAD and is interpreted as variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/640499/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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