Submissions for variant NM_002439.5(MSH3):c.692C>T (p.Pro231Leu)

gnomAD frequency: 0.00004  dbSNP: rs201748817

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000810465	SCV000950665	uncertain significance	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 231 of the MSH3 protein (p.Pro231Leu). This variant is present in population databases (rs201748817, gnomAD 0.01%). 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: 654492). 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.
Sema4, Sema4	RCV002259024	SCV002536546	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-31	criteria provided, single submitter	curation
Ambry Genetics	RCV002259024	SCV002668221	uncertain significance	Hereditary cancer-predisposing syndrome	2024-02-27	criteria provided, single submitter	clinical testing	The p.P231L variant (also known as c.692C>T), located in coding exon 4 of the MSH3 gene, results from a C to T substitution at nucleotide position 692. The proline at codon 231 is replaced by leucine, an amino acid with 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.
Baylor Genetics	RCV003461195	SCV004197126	uncertain significance	Endometrial carcinoma	2023-12-25	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000810465	SCV004221119	uncertain significance	not provided	2023-07-03	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, 0.000026 (3/113734 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.
Breakthrough Genomics, Breakthrough Genomics	RCV000810465	SCV005188849	uncertain significance	not provided		criteria provided, single submitter	not provided
Fulgent Genetics, Fulgent Genetics	RCV005036185	SCV005673167	uncertain significance	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-03-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003892731	SCV004713481	uncertain significance	MSH3-related disorder	2023-11-27	no assertion criteria provided	clinical testing	The MSH3 c.692C>T variant is predicted to result in the amino acid substitution p.Pro231Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.