Submissions for variant NM_000179.3(MSH6):c.3557-3A>T

gnomAD frequency: 0.00004  dbSNP: rs41295274

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074883	SCV000108096	benign	Lynch syndrome	2015-01-09	reviewed by expert panel	research
Ambry Genetics	RCV000131722	SCV000186762	benign	Hereditary cancer-predisposing syndrome	2019-04-11	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
Invitae	RCV000524180	SCV000260084	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001094686	SCV000430977	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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000506076	SCV000601578	benign	not specified	2017-02-11	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131722	SCV000685414	benign	Hereditary cancer-predisposing syndrome	2022-01-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000506076	SCV000917781	benign	not specified	2018-10-23	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3557-3A>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. These predictions were confirmed as the variant was found to not affect mRNA splicing or protein expression (Barnetson_2008). The variant allele was found at a frequency of 0.00034 in 230238 control chromosomes, predominantly at a frequency of 0.0024 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 17-folds higher than 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. c.3557-3A>T has been reported in the literature an individuals affected with colorectal cancer (Barnetson_2008). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant five times as likely benign/benign and once as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
GeneDx	RCV001711171	SCV001940731	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000131722	SCV002528045	likely benign	Hereditary cancer-predisposing syndrome	2021-08-10	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000506076	SCV004024808	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004542744	SCV004778107	likely benign	MSH6-related disorder	2019-03-29	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	RCV001357440	SCV001552914	likely benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 c.3557-3A>T variant was identified in 1 of 1864 proband chromosomes (frequency: 0.001) from individuals or families with colorectal cancer and was not identified in 2242 control chromosomes from healthy individuals (Barnetson 2008). The variant was also identified in the following databases: dbSNP (ID: rs41295274), ClinVar (classified as benign by Insight, Color Genomics, QDNISJC; classified as likely benign by Ambry Genetics, Invitae), Clinvitae, Cosmic, UMD-LSDB (1X as neutral), Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (class1). The variant was not identified in the COGR or Zhejiang Colon Cancer Database. The variant was identified in control databases in 79 of 230238 chromosomes at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: Other in 2 of 4924 chromosomes (freq: 0.0004), Latino in 2 of 30982 chromosomes (freq: 0.0001), European in 10 of 105232 chromosomes (freq: 0.0001), and South Asian in 65 of 27326 chromosomes (freq: 0.002); it was not observed in the African, Ashkenazi Jewish, East Asian, or Finnish populations. The c.3557-3A>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In addition, 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, RNA analysis for exon skipping in population study by Barnetson (2008) showed the variant has no effect on mRNA splicing or protein expression. In summary, based on the above information this variant meets our laboratory's criteria to be classified as likely benign.