ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3974A>T (p.Lys1325Met)

dbSNP: rs876658189
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000215262 SCV000273567 uncertain significance Hereditary cancer-predisposing syndrome 2023-01-10 criteria provided, single submitter clinical testing The p.K1325M variant (also known as c.3974A>T), located in coding exon 9 of the MSH6 gene, results from an A to T substitution at nucleotide position 3974. The lysine at codon 1325 is replaced by methionine, an amino acid with similar properties. This amino acid position is not well 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.
Color Diagnostics, LLC DBA Color Health RCV000215262 SCV000537550 uncertain significance Hereditary cancer-predisposing syndrome 2023-08-17 criteria provided, single submitter clinical testing This missense variant replaces lysine with methionine at codon 1325 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-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.
GeneDx RCV000485930 SCV000566508 uncertain significance not provided 2023-10-24 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports 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, 21120944, 17531815)
Labcorp Genetics (formerly Invitae), Labcorp RCV000697066 SCV000825656 benign Hereditary nonpolyposis colorectal neoplasms 2025-01-26 criteria provided, single submitter clinical testing
Baylor Genetics RCV003462423 SCV004195590 uncertain significance Endometrial carcinoma 2023-08-14 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997805 SCV004835180 uncertain significance Lynch syndrome 2024-06-09 criteria provided, single submitter clinical testing This missense variant replaces lysine with methionine at codon 1325 of the MSH6 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-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.
Clinical Genetics Laboratory, Skane University Hospital Lund RCV000485930 SCV005199220 uncertain significance not provided 2022-05-27 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485930 SCV005623501 uncertain significance not provided 2024-12-07 criteria provided, single submitter clinical testing The MSH6 c.3974A>T (p.Lys1325Met) variant has been reported in the published literature in a large scale breast cancer association study in both breast cancer cases and reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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