ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3313G>A (p.Gly1105Arg)

gnomAD frequency: 0.00001  dbSNP: rs755716475
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220326 SCV000273594 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-20 criteria provided, single submitter clinical testing The p.G1105R variant (also known as c.3313G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3313. The glycine at codon 1105 is replaced by arginine, an amino acid with dissimilar 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV000461508 SCV000551188 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-01-25 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000220326 SCV000908416 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-15 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 1105 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.
CeGaT Center for Human Genetics Tuebingen RCV003422122 SCV004146080 uncertain significance not provided 2023-10-01 criteria provided, single submitter clinical testing MSH6: PM2, PP3, BP1
GeneDx RCV003422122 SCV005079638 uncertain significance not provided 2024-02-14 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with colorectal and breast cancer (PMID: 37460658); This variant is associated with the following publications: (PMID: 17531815, 21120944, 37460658)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000220326 SCV005415595 uncertain significance Hereditary cancer-predisposing syndrome 2024-10-15 criteria provided, single submitter clinical testing The missense variant NM_000179.3(MSH6):c.3313G>A (p.Gly1105Arg) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The p.Gly1105Arg variant is observed in 2/113,724 (0.0018%) alleles from individuals of gnomAD Non Finnish European background in gnomAD. The p.Gly1105Arg variant is novel (not in any individuals) in 1kG. There is a moderate physicochemical difference between glycine and arginine. The p.Gly1105Arg missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 1105 of MSH6 is conserved in all mammalian species. The nucleotide c.3313 in MSH6 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance
All of Us Research Program, National Institutes of Health RCV004806219 SCV005429409 uncertain significance Lynch syndrome 2024-08-06 criteria provided, single submitter clinical testing This missense variant replaces glycine with arginine at codon 1105 of the MSH6 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 3/282720 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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.

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