ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.884A>G (p.Lys295Arg) (rs267608051)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115445 SCV000214730 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CeGaT Praxis fuer Humangenetik Tuebingen RCV000512927 SCV000608936 uncertain significance not provided 2017-05-31 criteria provided, single submitter clinical testing
Color RCV000115445 SCV000910671 likely benign Hereditary cancer-predisposing syndrome 2014-12-09 criteria provided, single submitter clinical testing
Counsyl RCV000410872 SCV000487810 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-11-18 criteria provided, single submitter clinical testing
GeneDx RCV000512927 SCV000149354 uncertain significance not provided 2018-11-16 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.884A>G at the cDNA level, p.Lys295Arg (K295R) at the protein level, and results in the change of a Lysine to an Arginine (AAA>AGA). This variant was reported in individuals with multiple colorectal polyps or colon cancer, in one proband from a Lynch syndrome family, and in at least two individuals with ovarian cancer (Colley 2005, Nilbert 2009, Pal 2012, Lu 2015, Shirts 2016). Gassman et al. (2011) demonstrated no significant defect in nuclear accumulation of the MSH6 protein due to Lys295Arg, suggesting that this variant does not interfere with nuclear protein transport. MSH6 Lys295Arg was observed at an allele frequency of 0.018% (23/126,552) in individuals of European ancestry in large population cohorts (Lek 2016). MSH6 Lys295Arg is located in the nuclear localization signal region (Gassman 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Lys295Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000512927 SCV000695929 uncertain significance not provided 2017-06-05 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.884A>G variant affects a conserved nucleotide, resulting in amino acid change from Lys to Arg. 3/5 in-silico tools predict this variant to be damaging. However, these predictions have yet to be confirmed by functional studies. This variant has been reported in multiple patients with lynch syndrome or ovarian cancer, however without strong evidence for pathogenicity. This variant was found in 12/121142 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00018 (12/66598). This frequency is about 1 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is possibly a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. One study showed that this variant did not affect MSH6 localization; however whether the variant is proficient in mismatch repair was not addressed. In addition, multiple clinical laboratories/reputable databases classified this variant as VUS. Taken together, this variant is currently classified as VUS until more evidence becomes available.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075042 SCV000108263 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000524217 SCV000254335 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 295 of the MSH6 protein (p.Lys295Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs267608051, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has been reported in individuals affected with Lynch syndrome, multiple colorectal adenomas, ovarian cancer, and colon cancer (PMID: 16010685, 18566915, 23047549, 26845104). ClinVar contains an entry for this variant (Variation ID: 89573). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). Furthermore, an experimental in vitro study has shown that this variant does not disrupt MSH6 stability and localization (PMID: 21437237). 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.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000212636 SCV000539701 uncertain significance not specified 2016-03-28 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper, no segs, ExAC: 0.02% (12/66598) European chromosomes
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212636 SCV000601619 uncertain significance not specified 2016-10-13 criteria provided, single submitter clinical testing
University of Washington Department of Laboratory Medicine,University of Washington RCV000075042 SCV000266213 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing

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