ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3969T>G (p.Phe1323Leu)

dbSNP: rs1057520473
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480171 SCV000567800 uncertain significance not provided 2024-05-22 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 12019211, 17531815, 21120944)
Ambry Genetics RCV001021548 SCV001183175 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-17 criteria provided, single submitter clinical testing The p.F1323L variant (also known as c.3969T>G), located in coding exon 9 of the MSH6 gene, results from a T to G substitution at nucleotide position 3969. The phenylalanine at codon 1323 is replaced by leucine, an amino acid with highly 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.
Institute of Human Genetics, University of Leipzig Medical Center RCV001262331 SCV001440155 uncertain significance Breast carcinoma 2019-01-01 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001350960 SCV001545388 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2024-01-05 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 1323 of the MSH6 protein (p.Phe1323Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 419767). 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 MSH6 protein function with a negative predictive value of 95%. 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.
Baylor Genetics RCV003464001 SCV004195685 uncertain significance Endometrial carcinoma 2023-07-04 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002313 SCV004821997 uncertain significance Lynch syndrome 2024-01-11 criteria provided, single submitter clinical testing

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