Submissions for variant NM_000179.3(MSH6):c.3227G>A (p.Arg1076His)

gnomAD frequency: 0.00001  dbSNP: rs779617676

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165943	SCV000216699	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-08	criteria provided, single submitter	clinical testing	The p.R1076H variant (also known as c.3227G>A), located in coding exon 5 of the MSH6 gene, results from a G to A substitution at nucleotide position 3227. The arginine at codon 1076 is replaced by histidine, an amino acid with highly similar properties. This alteration has been identified in multiple individuals whose Lynch syndrome-associated tumors displayed isolated loss of MSH6 on immunohistochemistry (IHC) and/or had high microsatellite instability (MSI-H) (Ambry internal data). This alteration was reported in one family from a cohort of 59 Asian families meeting Amsterdam I or Amsterdam II criteria (Liu Y et al. PLoS ONE. 2014 Apr;9:e94170). This alteration has also been reported in multiple patients with a personal/family history of breast and/or ovarian cancer and patients with pancreatic cancer (Wong ESY et al. NPJ Genom. Med. 2016 Jan 13;1:15003; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-817; Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390; Hu H et al. J Am Coll Surg. 2020 11;231:527-535.e14). Another alteration at the same amino acid position, p.R1076C, has been reported as likely pathogenic due to its identification in individuals with clinical features of hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and constitutional mismatch repair deficiency (CMMRD) syndrome (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; Schofield L et al. Int. J .Cancer. 2009 Sep;125:1492-3; Jasperson KW et al. Clin. Genet. 2011 Oct;80:394-7; Gardès P et al. J. Immunol. 2012 Feb;188:2023-9). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000198283	SCV000254307	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2024-01-05	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1076 of the MSH6 protein (p.Arg1076His). This variant is present in population databases (rs779617676, gnomAD 0.002%). This missense change has been observed in individuals with Lynch syndrome and/or MSH6-related conditions (PMID: 24710284, 26898890, 31997046; external communication). ClinVar contains an entry for this variant (Variation ID: 186361). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MSH6 protein function. 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, 18566915, 21039432; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202247	SCV000695845	uncertain significance	not specified	2024-07-17	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3227G>A (p.Arg1076His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251346 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3227G>A has been reported in the literature in affected individuals, observed as both germline and assumed somatic occurrences; however, co-occurrence and cosegregation data are very limited (Caminsky_2016, Liu_2014, Maxwell_2016, Li_2020, Shindo_2017). These data do not allow any conclusion about variant significance. Two publications report experimental evidence evaluating an impact on protein function, however, none of these studies allows convincing conclusions about the variant effect (Seshagiri_2012, Schrader_2016). The following publications have been ascertained in the context of this evaluation (PMID: 22895193, 26556299, 26898890, 31391288, 24710284, 27153395, 28767289). ClinVar contains an entry for this variant (Variation ID: 186361). Based on the evidence outlined above, the variant was classified as uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000165943	SCV001345225	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-10-19	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine 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 performed for this variant. This variant has been reported in individuals affected with Lynch syndrome, pancreatic, colorectal, and breast and/or ovarian cancers (PMID: 24710284, 26898890, 27153395, 29263802, 28767289, 37088804; ClinVar: SCV000216699.6). Different variants occurring at the same codon, c.3226C>T (p.Arg1076Cys) and c.3226C>G (p.Arg1076Gly), are well-documented pathogenic mutations (ClinVar Variation ID: 89357, 428337). This variant has been identified in 2/251346 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	RCV000588416	SCV003833649	likely pathogenic	not provided	2022-11-08	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003462194	SCV004195783	likely pathogenic	Endometrial carcinoma	2023-05-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000165943	SCV005045363	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-23	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202247	SCV000257243	uncertain significance	not specified		flagged submission	research
University of Washington Department of Laboratory Medicine, University of Washington	RCV000758680	SCV000887452	uncertain significance	Lynch syndrome	2018-05-01	flagged submission	clinical testing	MSH6 NM_000179.2:c.3227G>A has a 58.2% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 0.16 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.