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

gnomAD frequency: 0.00003  dbSNP: rs188074706

Total submissions: 8

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.