ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.335A>G (p.Asn112Ser) (rs587779934)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000656887 SCV000149323 uncertain significance not provided 2018-11-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.335A>G at the cDNA level, p.Asn112Ser (N112S) at the protein level, and results in the change of an Asparagine to a Serine (AAC>AGC). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH6 Asn112Serwas not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Asn112Ser is not located in a known functional domain. While protein-based in silico analysis supports that this variant does not alter protein structure/function, splicing models predict the creation of a novel splice site. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available information, it is unclear whether MSH6 Asn112Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000524173 SCV000166229 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 112 of the MSH6 protein (p.Asn112Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs587779934, ExAC 0.01%). This variant has been reported in an individual in the Universal Mutation Database (PMID: 23729658), and an individual affected with rectal cancer (Invitae). However, in these individuals pathogenic alleles were also identified in MLH1 and MSH6, respectively, which suggests that this c.335A>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 127586). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Ambry Genetics RCV000115414 SCV000214649 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Illumina Clinical Services Laboratory,Illumina RCV000122964 SCV000430950 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Color RCV000115414 SCV000685394 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000212629 SCV000731369 uncertain significance not specified 2017-01-25 criteria provided, single submitter clinical testing The p.Asn112Ser variant in MSH6 has not been previously reported in individuals with Lynch syndrome. This variant has been identified in 1/10406 of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs587779934). Computational prediction tools and conservation analysis suggest that the p.Asn112Ser variant may not impact the protein, though this inf ormation is not predictive enough to rule out pathogenicity. In summary, the cli nical significance of the p.Asn112Ser variant is uncertain.

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