ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2827G>T (p.Asp943Tyr) (rs143520357)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131640 SCV000186664 likely benign Hereditary cancer-predisposing syndrome 2019-08-15 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Other data supporting benign classification;Other strong data supporting benign classification;Rare (0.1%) in general population databases (dbsnp, esp, 1000 genomes)
GeneDx RCV000212672 SCV000211303 uncertain significance not provided 2016-11-18 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2827G>T at the cDNA level, p.Asp943Tyr (D943Y) at the protein level, and results in the change of an Aspartic Acid to a Tyrosine (GAC>TAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Asp943Tyr was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Aspartic Acid and Tyrosine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Asp943Tyr occurs at a position that is conserved through mammals and is located within the MutS domain IV (Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Asp943Tyr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000205918 SCV000261184 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with tyrosine at codon 943 of the MSH6 protein (p.Asp943Tyr). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. This variant is present in population databases (rs143520357, ExAC 0.006%). This variant has been reported in individuals affected with breast cancer (PMID: 25186627) and pancreatic cancer (PMID: 25479140). ClinVar contains an entry for this variant (Variation ID: 142495). 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: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C1). However, an algorithm developed specifically for the MSH6 protein suggests that this missense change is likely to be deleterious (PMID: 23621914). None of these predictions have been confirmed by published functional 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. 5
Counsyl RCV000412088 SCV000489142 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131640 SCV000537570 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-24 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356309 SCV001551439 uncertain significance Lynch syndrome no assertion criteria provided clinical testing The MSH6 p.Asp943Tyr variant was identified in 1 of 580 proband chromosomes (frequency: 0.002) from individuals or families with pancreatic cancer (Grant_2015_25479140). A bioinformatics tool, CoDP (Combination of the Different Properties) integrating the prediction results of three methods (MAPP, PolyPhen-2 and SIFT) and two structural properties, found the variant impacted the MSH6 protein (Terui_2013_23621914). The variant was also identified in dbSNP (ID: rs143520357) “With Uncertain significance allele”, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl, Color Genomics), Clinvitae (4x), and in control databases in 13 of 276196 chromosomes at a frequency of 0.00005 (Genome Aggregation Database Feb 27, 2017). It was identified in the European Non-Finnish population in 13 of 125940 chromosomes (freq: 0.0001); and was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish and South Asian populations. The variant was not identified in the COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database or the Insight Hereditary Tumors Database. The p.Asp943 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Tyr variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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