Submissions for variant NM_000179.3(MSH6):c.3946G>C (p.Gly1316Arg)

dbSNP: rs773675555

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221062	SCV000279986	uncertain significance	not provided	2018-09-07	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3946G>C at the cDNA level, p.Gly1316Arg (G1316R) at the protein level, and results in the change of a Glycine to an Arginine (GGA>CGA). Although this variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant, a different nucleotide change at the same position, MSH6 c.3946G>A, which also results in MSH6 Gly1316Arg, has been reported in the homozygous state in an individual with constitutional mismatch repair deficiency syndrome (Bakry 2014). MSH6 Gly1316Arg was not observed in large population cohorts (Lek 2016). This variant is located in the ATPase domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Gly1316Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001205042	SCV001376278	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2022-06-04	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Gly1316 amino acid residue in MSH6. Other variant(s) that disrupt this residue have been observed in individuals with MSH6-related conditions (PMID: 24100870, 24440087), which suggests that this may be a clinically significant amino acid residue. 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: 234901). This missense change has been observed in individual(s) with clinical features of constitutional mismatch repair deficiency syndrome (PMID: 24440087, 30608896). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1316 of the MSH6 protein (p.Gly1316Arg).
Ambry Genetics	RCV002354622	SCV002621010	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-25	criteria provided, single submitter	clinical testing	The p.G1316R variant (also known as c.3946G>C), located in coding exon 9 of the MSH6 gene, results from a G to C substitution at nucleotide position 3946. The glycine at codon 1316 is replaced by arginine, an amino acid with dissimilar properties. A different nucleotide change at this position (c.3946G>A) coding for the same amino acid change (p.G1316R) has been identified in the homozygous state in a male with constitutional mismatch repair deficiency (CMMR-D), having a diagnosis of anaplastic astrocytoma and cafe-au-lait spots at age 11 (Bakry D et al. Eur. J. Cancer, 2014 Mar;50:987-96). Based on an internal structural assessment, this alteration results in disruption of the C-terminal MSH2-MSH6 interface (Warren JJ et al. Mol. Cell, 2007 May;26:579-92). 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.
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003333744	SCV004041683	likely pathogenic	Lynch syndrome 5	2023-10-09	no assertion criteria provided	clinical testing