Submissions for variant NM_000179.3(MSH6):c.3354G>A (p.Glu1118=)

dbSNP: rs35642130

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001086511	SCV000261838	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000429486	SCV000516862	benign	not specified	2015-05-18	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000491525	SCV000580266	likely benign	Hereditary cancer-predisposing syndrome	2015-05-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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	RCV000491525	SCV000685393	benign	Hereditary cancer-predisposing syndrome	2016-11-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000429486	SCV000919765	benign	not specified	2018-04-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3354G>A alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00043 in 246174 control chromosomes, predominantly at a frequency of 0.0034 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 23.93 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.3354G>A in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000206593	SCV001134428	benign	not provided	2019-07-12	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001137559	SCV001297511	uncertain significance	Lynch syndrome 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Genetic Services Laboratory, University of Chicago	RCV000429486	SCV002066179	likely benign	not specified	2018-03-06	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491525	SCV002528014	benign	Hereditary cancer-predisposing syndrome	2021-05-20	criteria provided, single submitter	curation
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV001137559	SCV004015993	benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000429486	SCV001549145	benign	not specified		no assertion criteria provided	clinical testing	The MSH6 p.Glu1118= variant was not identified in the literature nor was it identified in the following databases: GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs35642130) “With Likely benign allele”, ClinVar (classified benign by Invitae, GeneDx and likely benign by Ambry Genetics), Clinvitae (3x), and in control databases in 106 (3 homozygous) of 246174 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European Non-Finnish in 1 of 111648 chromosomes (freq: 0.000009), and South Asian in 105 (3 homozygous) of 30782 chromosomes (freq: 0.003), while not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, or European Finnish populations. The p.Glu1118= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site, with 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicting a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.