ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3226C>G (p.Arg1076Gly) (rs63750617)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000491655 SCV000580189 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing The p.R1076G variant (also known as c.3226C>G), located in coding exon 5 of the MSH6 gene, results from a C to G substitution at nucleotide position 3226. The arginine at codon 1076 is replaced by glycine, an amino acid with dissimilar properties. This alteration has been identified in several individuals who either met clinical criteria for Lynch syndrome or had Lynch syndrome-associated tumors that demonstrated isolated loss of MSH6 protein expression by immunohistochemistry (Ambry internal data). This alteration was identified in 1/1260 individuals undergoing panel testing for Lynch syndrome due to having a diagnosis of a Lynch-associated cancer and/or polyps and was reported as a variant of unknown significance (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20). Another alteration at the same codon, p.R1076C, has been classified as likely pathogen based on reports of at least five probands with features of CMMR-D who also carried a pathogenic (nonsense/frameshift) MSH6 variant in trans, which suggested bi-allelic mismatch repair inactivation (Plaschke J et al. Eur. J. Hum. Genet. 2006 May;14:561-6; Okkels H et al. Int J Colorectal Dis. 2006 Dec;21:847-50; Rahner N et al. Am. J. Med. Genet. A. 2008 May;146A:1314-9; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000629920 SCV000750876 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2018-07-13 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 1076 of the MSH6 protein (p.Arg1076Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is present in population databases (rs63750617, ExAC 0.001%). This variant has been reported in an individual in the Leiden Open-source Variation Database (PMID: 21520333). ClinVar contains an entry for this variant (Variation ID: 428337). 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. A different missense substitution at this codon (p.Arg1076Cys) has been determined to be pathogenic (PMID: 15483016, 16418736, 16525781, 21039432, 18409202). This suggests that the arginine residue is critical for MSH6 protein function and that other missense substitutions at this position may also be pathogenic. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759862 SCV000889488 uncertain significance not provided 2018-03-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000491655 SCV001353070 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000504512 SCV000592627 uncertain significance Lynch syndrome no assertion criteria provided clinical testing The p.Arg1076Gly has not been previously reported in the literature or by our laboratory. However, another variant at the same position (c.3226C>T, p.Arg1076Cys) has been reported in 4 individuals, at least 2 of whom had biallelic mutations in the MSH6 gene and in several individuals where microsattelite instability was high and tumour immunohistochemistry demonstrated that MSH6 was deficient (Rahner 2007, Jasperson 2010, Limburg 2011, Plaschke, 2004). In one family with MSH6 biallelic mutations and NF1 like phenotypic features, the p.Arg1076Cys variant segregated with disease in one sibling (Jasperson, 2010_21039432). In another with biallelic MSH6 mutations, the p.Arg1076Cys variant, classic features of biallelic mutations in MSH6 were not observed but early onset colon cancer and SLE was noted (Rahner, 2007_18409202). These findings increase the likelihood that a change in amino acid at the p.Arg1076 position may have clinical significance and that this residue is functionally important. The residue is conserved in mammals, birds and reptiles but not in all invertebrates and computational analyses do not provide consistent predictions regarding the significance of this amino acid alteration and this information is not very helpful in classifying the variant. It should be noted that this individual was identified as being MSH6 deficient from a tumour, increasing the likelihood that this alteration may have clinical significance. In summary, based on the above information, the clinical significance of this particular variant: p.Arg1076Gly cannot be determined at this time, although we would lean towards a more pathogenic role, further study would be necessary to evaluate this. This variant is classified as a variant of unknown significance.

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