Submissions for variant NM_000179.3(MSH6):c.3226C>G (p.Arg1076Gly)

dbSNP: rs63750617

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000491655	SCV000580189	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-01	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 pathogenic 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, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae	RCV000629920	SCV000750876	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-06-11	criteria provided, single submitter	clinical testing	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 expected to disrupt MSH6 protein function. ClinVar contains an entry for this variant (Variation ID: 428337). This missense change has been observed in individuals with Lynch syndrome (PMID: 25980754, 30702970; external communication). This variant is present in population databases (rs63750617, gnomAD 0.0009%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 1076 of the MSH6 protein (p.Arg1076Gly). This variant disrupts the p.Arg1076 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15483016, 16418736, 16525781, 18409202, 21039432). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759862	SCV000889488	uncertain significance	not provided	2018-03-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491655	SCV001353070	likely pathogenic	Hereditary cancer-predisposing syndrome	2021-07-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glycine at codon 1076 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having Lynch syndrome (PMID: 25980754; communication with external laboratory: SCV000580189) and in an individual with unspecified cancer (PMID: 31391288). A different missense substitution at this codon (p.Arg1076Cys) has been determined to be pathogenic (Clinvar Variant ID: 89357), which suggests this variant occurs in a critical amino acid. This variant has been identified in 1/251346 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Revvity Omics, Revvity	RCV000759862	SCV003833199	likely pathogenic	not provided	2022-11-21	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.