ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3647-6T>A

gnomAD frequency: 0.00134  dbSNP: rs182871847
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115418 SCV000149327 likely benign not specified 2017-09-28 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.
Invitae RCV001081821 SCV000252629 benign Hereditary nonpolyposis colorectal neoplasms 2021-12-17 criteria provided, single submitter clinical testing
Genetic Services Laboratory,University of Chicago RCV000115418 SCV000595843 likely benign not specified 2019-07-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115418 SCV000601581 benign not specified 2016-11-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000579665 SCV000685425 likely benign Hereditary cancer-predisposing syndrome 2015-04-07 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587059 SCV000695881 benign not provided 2016-10-06 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.3647-6T>A variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predict no significant impact on normal splicing, which a reputable database reports in vitro and ex vivo analyses that support these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 47/120200 (1/2557), predominantly in the African cohort, 42/10262 (1/244), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. The variant of interest has been reported by multiple clinical diagnostic laboratories/databases with conflicting classifications "Benign/Likely Benign/Uncertain Significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
Counsyl RCV000662552 SCV000785135 likely benign Colorectal cancer, hereditary nonpolyposis, type 5 2017-05-04 criteria provided, single submitter clinical testing
Illumina Laboratory Services,Illumina RCV000662552 SCV001299976 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 5 2019-10-28 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.
Sema4,Sema4 RCV000579665 SCV002528053 benign Hereditary cancer-predisposing syndrome 2020-10-23 criteria provided, single submitter curation
True Health Diagnostics RCV000579665 SCV000788051 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357466 SCV001552947 likely benign Endometrial carcinoma no assertion criteria provided clinical testing The MSH6 c.3647-6T>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs182871847) as "With Likely benign, other allele", ClinVar (classified as benign by Invitae and two clinical laboratories; as likely benign by GeneDx, Color and Councyl; as uncertain significance by two submitters), and in UMD-LSDB (1x as likely neutral). The variant was identified in control databases in 117 of 276924 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 107 of 24034 chromosomes (freq: 0.005), Other in 1 of 6444 chromosomes (freq: 0.0002), Latino in 9 of 34364 chromosomes (freq: 0.0003), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.3647-6T>A 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, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000115418 SCV002552354 benign not specified 2021-10-19 no assertion criteria provided clinical testing

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