ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3557-3A>T (rs41295274)

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Total submissions: 7
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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 Other data supporting benign classification;Intronic alteration with no splicing impact by rt-pcr analysis or other splicing assay
Invitae RCV000524180 SCV000260084 likely benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001094686 SCV000430977 uncertain significance Hereditary nonpolyposis colorectal cancer type 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 RCV000131722 SCV000685414 benign Hereditary cancer-predisposing syndrome 2016-09-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America 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.

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