Submissions for variant NM_000179.3(MSH6):c.4002-10T>A

gnomAD frequency: 0.00026  dbSNP: rs545466048

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081736	SCV000166235	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000590285	SCV000211331	likely benign	not provided	2019-04-01	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30306255, 25561518, 26181448, 21056691)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000160702	SCV000539708	uncertain significance	not specified	2016-06-16	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 1 paper in HGMD describes as VUS; ClinVar: 1LB; Unlikely to impact splicing
Genetic Services Laboratory, University of Chicago	RCV000160702	SCV000595857	uncertain significance	not specified	2017-02-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000590285	SCV000601600	likely benign	not provided	2019-10-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160702	SCV000695909	benign	not specified	2019-05-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4002-10T>A alters a non-conserved nucleotide. 4/5 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 0.00026 in 244976 control chromosomes (gnomAD). The observed variant frequency is approximately 1.8 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 benign. The variant, c.4002-10T>A, has been reported in the literature in colorectal, gastric or breast cancer patients without strong evidence for causality (Limburg_2011, Yamashita_2013, Bonache_2018). A co-occurrence with another pathogenic variant has been reported (MSH6 c.3477C>G, p.Tyr1159X; internal testing), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven submitters have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS (n=5), Likely benign (n=1), Benign (n=1)) and one expert panel, InSiGHT, classified as uncertain significance before 2014. Based on the evidence outlined above, the variant was classified as benign.
Color Diagnostics, LLC DBA Color Health	RCV000771079	SCV000902614	likely benign	Hereditary cancer-predisposing syndrome	2015-12-28	criteria provided, single submitter	clinical testing
Mendelics	RCV000986753	SCV001135868	benign	Lynch syndrome 5	2023-08-22	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000590285	SCV001152304	uncertain significance	not provided	2017-12-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000986753	SCV001300825	uncertain significance	Lynch syndrome 5	2019-04-18	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Institute of Human Genetics, University Hospital Muenster	RCV002287361	SCV002577759	uncertain significance	See cases	2021-05-21	criteria provided, single submitter	clinical testing	ACMG categories: PM2,PP3
Ambry Genetics	RCV000771079	SCV002625351	likely benign	Hereditary cancer-predisposing syndrome	2016-04-27	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149725	SCV003838333	likely benign	Breast and/or ovarian cancer	2022-03-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000160702	SCV004024826	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003964920	SCV004784993	likely benign	MSH6-related condition	2023-01-27	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357666	SCV001553196	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6, c.4002-10T>A, r.(spl?) variant was identified in 31 of 48 proband chromosomes (frequency: 0.6) from individuals or families with familial colorectal cancer (Lucci-Cordisco 2001). The variant was also identified in dbSNP (ID: rs545466048) as “With Uncertain significance allele”, ClinVar (1x likely benign: Invitae; 3x uncertain significance: InSiGHT, GeneDx, Partners HealthCare), COSMIC (1x confirmed somatic in Wilms tumour of kidney), UMD-LSDB (biological significance neutral; variation in splice site consensus value <10%), Insight Colon Cancer Gene Variant Database (3x uncertain significance), Mismatch Repair Genes Variant Database (as c.4002-8dupA polymorphism in Verma 1999 and Lucci-Cordisco 2001, describing this as a poly A expansion where “sequencing suggests that different length variants exist or are highly prone to stuttering so that it is not possible to sequence across them"), Insight Hereditary Tumors Database (3x effect unknown), databases. The variant was not identified in MutDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 57 of 213460 chromosomes at a frequency of 0.0003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000590285	SCV002036795	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000590285	SCV002037221	likely benign	not provided		no assertion criteria provided	clinical testing