ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.4001G>C (p.Arg1334Pro) (rs267608122)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000219938 SCV000277547 likely pathogenic Hereditary cancer-predisposing syndrome 2015-08-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Last nucleotide of exon,Rarity in general population databases (dbsnp, esp, 1000 genomes)
Invitae RCV000459481 SCV000551274 uncertain significance Hereditary nonpolyposis colon cancer 2017-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with proline at codon 1334 of the MSH6 protein (p.Arg1334Pro). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and proline. It also falls at the last nucleotide of exon 9 of the MSH6 coding sequence. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 233214). A different missense substitution at this codon (c.4001G>A; p.Arg1334Gln) has been reported in individuals and families affected with Lynch syndrome and is likely pathogenic (PMID: 10508506, 17453009, 21836479, 18415027). This suggests that the c.4001G nucleotide is crucial for normal RNA splicing or the arginine residue is critical for MSH6 protein function and that this missense change may also be pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a rare missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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