ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1061G>T (p.Gly354Val) (rs730881788)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212644 SCV000211272 uncertain significance not provided 2017-05-05 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1061G>T at the cDNA level, p.Gly354Val (G354V) at the protein level, and results in the change of a Glycine to a Valine (GGA>GTA). This variant has been observed in at least one individual with early onset breast cancer (Maxwell 2015). MSH6 Gly354Val was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glycine and Valine share similar properties, this is considered a conservative amino acid substitution. MSH6 Gly354Val occurs at a position that is conserved in mammals and is located in the region containing the nuclear localization signals (Gassman 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Splicing models suggest that this variant may result in a cryptic splice donor site upstream of the natural site. Based on currently available information, it is unclear whether MSH6 Gly354Val is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160663 SCV000215588 uncertain significance Hereditary cancer-predisposing syndrome 2015-12-04 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000198861 SCV000254270 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with valine at codon 354 of the MSH6 protein (p.Gly354Val). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and valine. This variant is present in population databases (rs730881788, ExAC 0.01%). This variant has been reported in two individuals affected with early-onset breast cancer (PMID: 24362816, 25503501). ClinVar contains an entry for this variant (Variation ID: 182618). 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 tolerated, but these predictions have not been confirmed by published functional studies. 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 RCV000662570 SCV000785177 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-05-26 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000212644 SCV000885720 uncertain significance not provided 2018-05-21 criteria provided, single submitter clinical testing The MSH6 c.1061G>T; p.Gly354Val variant (rs730881788), is reported in the literature in at least one individual with early-onset breast cancer (Maxwell 2015). This variant is reported as uncertain in ClinVar (Variation ID: 182618), and found in the general population with a low overall allele frequency of 0.003% (1/30980 alleles) in the Genome Aggregation Database. The glycine at codon 354 is not highly conserved, and computational programs that predict the effect of missense variants on the protein (SIFT, PolyPhen-2) suggest that this variant is tolerated. However, splicing algorithms (Alamut v.2.11) suggest this variant may have an impact on splicing by creating a cryptic donor site. Due to limited information, the clinical significance of the p.Gly354Val variant is uncertain at this time. REFERENCES Maxwell KN et al. Prevalence of mutations in a panel of breast cancer susceptibility genes in BRCA1/2-negative patients with early-onset breast cancer. Genet Med. 2015 Aug;17(8):630-8.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212644 SCV000889451 uncertain significance not provided 2018-01-05 criteria provided, single submitter clinical testing
Color RCV000160663 SCV000911840 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing

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