ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.650A>G (p.Asp217Gly) (rs554012110)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131354 SCV000186329 likely benign Hereditary cancer-predisposing syndrome 2020-07-20 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000212632 SCV000211258 likely benign not provided 2021-02-01 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 23047549, 28944238)
Invitae RCV000167904 SCV000218552 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-18 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 217 of the MSH6 protein (p.Asp217Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs554012110, ExAC 0.04%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with ovarian cancer and colorectal cancer (PMID: 23047549, 28944238). ClinVar contains an entry for this variant (Variation ID: 142305). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MSH6 protein function. Algorithms developed to predict the effect of sequence 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, 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.
Counsyl RCV000411184 SCV000489127 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-08-22 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131354 SCV000685512 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-09 criteria provided, single submitter clinical testing This missense variant replaces aspartic acid with glycine at codon 217 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in one individual each affected with ovarian cancer (PMID: 23047549) and childhood-onset leukemia (PMID: 26580448). This variant has been identified in 20/279280 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The 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.
Mendelics RCV000708856 SCV000837869 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212632 SCV001134454 uncertain significance not provided 2019-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001193124 SCV001361760 uncertain significance not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: MSH6 c.650A>G (p.Asp217Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 247868 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (7.7e-05 vs 0.00014), allowing no conclusion about variant significance. The variant, c.650A>G, has been reported in the literature in individuals affected with ovarian cancer, pediatric cancer or colorectal cancer (Pal_2012, Zhang_2015, DeRycke_2017). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355774 SCV001550749 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 p.Asp217Gly variant was identified in 1 of 3786 proband chromosomes (frequency: 0.0003) from individuals or families with ovarian cancer (Pal 2012). The variant was also identified in dbSNP (ID: rs554012110) as With Uncertain significance allele, ClinVar (classified as uncertain significance by Ambry Genetics, GeneDx, Invitae, Counsyl), databases. The variant was not identified in the GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, databases. The variant was identified in control databases in 20 of 273722 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 8 of 23898 chromosomes (freq: 0.0003), European Non-Finnish in 3 of 125846 chromosomes (freq: 0.00002), and South Asian in 9 of 30740 chromosomes (freq: 0.0003), while the variant was not observed in the Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, populations. The p.Asp217 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 4 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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.
GenomeConnect - Invitae Patient Insights Network RCV001535792 SCV001749951 not provided Hereditary nonpolyposis colon cancer no assertion provided phenotyping only Variant interpreted as Uncertain significance and reported on 02-10-2020 by Ambry Genetics. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.

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