Submissions for variant NM_000179.3(MSH6):c.2765G>A (p.Arg922Gln)

gnomAD frequency: 0.00001  dbSNP: rs752839086

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000461564	SCV000920448	likely benign	Lynch syndrome	2018-12-19	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability < 0.05 (0.028)
Invitae	RCV000791412	SCV000551263	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-14	criteria provided, single submitter	clinical testing
GeneDx	RCV000487150	SCV000572548	uncertain significance	not provided	2016-12-27	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.2765G>A at the cDNA level, p.Arg922Gln (R922Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). Although this variant has not been reported as a germline variant to our knowledge, MSH6 Arg922Gln has been published as a somatic variant in an endometrial tumor and gastric tumor (Wang 2011, Mehnert 2016).MSH6 Arg922Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH6 Arg922Gln occurs at a position that is not conserved and is located in domain III of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Arg922Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000563123	SCV000669915	likely benign	Hereditary cancer-predisposing syndrome	2021-06-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Color Diagnostics, LLC DBA Color Health	RCV000563123	SCV001342494	likely benign	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192425	SCV001360538	likely benign	not specified	2019-09-06	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.2765G>A (c.2765G>A) results in a conservative amino acid change located in the DNA mismatch repair protein MutS, core domain (IPR007696) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 250952 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2765G>A has been reported in the literature in individuals affected with colorectal cancer and Lynch Syndrome associated cancers (Houlleberghs_2017, Jun_2017). However, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrence with another pathogenic variant have been reported (MSH6 c.2805dup , p.Asp936X) in the literature for this variant (Houlleberghs_2017) , providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function. These results showed no damaging effect of this variant (Houlleberghs_2017). Four submitters including one expert panel (InSiGHT) have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (3x uncertain significance and 1x Likely benign-InSiGHT). Based on the evidence outlined above, the variant was classified as likely benign.