ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3334G>A (p.Asp1112Asn) (rs773955368)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000206715 SCV000261616 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 1112 of the MSH6 protein (p.Asp1112Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs773955368, ExAC 0.006%). This variant has been observed in an individual affected with renal cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 220784). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C1. The asparagine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. 5
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985259 SCV000601572 uncertain significance not provided 2019-08-19 criteria provided, single submitter clinical testing
Ambry Genetics RCV000571369 SCV000662372 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-18 criteria provided, single submitter clinical testing The p.D1112N variant (also known as c.3334G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3334. The aspartic acid at codon 1112 is replaced by asparagine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species; however, asparagine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000508319 SCV000712573 uncertain significance not specified 2016-11-15 criteria provided, single submitter clinical testing The p.Asp1112Asn variant in MSH6 has not been previously reported in individuals with colorectal cancer but has been identified in 4/66730 European chromosomes by the Exome Aggregation Consortium (ExAC,; dbSNP rs773955368). Computational prediction tools are ambiguous but multiple species (including one mammal) carry the variant amino acid, raising the possibility th at this change is tolerated. However this is insufficient to rule out a role in disease. In summary, the clinical significance of the p.Asp1112Asn variant is un certain.
Counsyl RCV000663075 SCV000786149 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-03-09 criteria provided, single submitter clinical testing
Color Health, Inc RCV000571369 SCV000910828 likely benign Hereditary cancer-predisposing syndrome 2016-03-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000508319 SCV000917754 uncertain significance not specified 2018-04-06 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3334G>A (p.Asp1112Asn) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.3e-05 in 121372 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (3.3e-05 vs 0.00014), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.3334G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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