ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.628-7C>A (rs373129248)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001080866 SCV000166236 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-02 criteria provided, single submitter clinical testing
Counsyl RCV000411528 SCV000487982 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588337 SCV000601612 uncertain significance not provided 2019-08-26 criteria provided, single submitter clinical testing
Color Health, Inc RCV000580986 SCV000685510 likely benign Hereditary cancer-predisposing syndrome 2015-04-22 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588337 SCV000695919 uncertain significance not provided 2017-05-26 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.628-7C>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 3/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 12/117788 control chromosomes, predominantly observed in the uropean (Non-Finnish) subpopulation at a frequency of 0.00017 (11/64642). This frequency is slightly higher than the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in one patient with Lynch syndrome without strong evidence for or against pathogenicity (Barrow_2010). In ClinVar while one clinical diagnostic laboratory has classified this variant as likely benign, another lab has classified it as VUS, both without evidence for independent evaluation. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance-possibly benign until additional information becomes available.
PreventionGenetics,PreventionGenetics RCV000588337 SCV000805907 likely benign not provided 2017-05-30 criteria provided, single submitter clinical testing
Mendelics RCV000411528 SCV001135792 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000411528 SCV001302616 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001287891 SCV001474635 uncertain significance none provided 2019-11-11 criteria provided, single submitter clinical testing The MSH6 c.628-7C>A variant (rs373129248) is reported in the literature in a single individual affected with Lynch syndrome (Barrow 2010). This variant is reported in ClinVar (Variation ID: 135843), and is found in the general population with an overall allele frequency of 0.0083% (23/275494 alleles) in the Genome Aggregation Database. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing weakening the nearby canonical acceptor splice site. However, without functional studies, the effect on splicing is unknown. Given the lack of clinical and functional data, the significance of the c.628-7C>A variant is uncertain at this time. References: Barrow E et al. Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome. Histopathology. 2010 Feb;56(3):331-44.
GeneDx RCV000588337 SCV001895732 benign not provided 2015-03-03 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 32634176)
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001356719 SCV001551962 uncertain significance Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 c.628-7C>A variant was identified in 1 of 102 proband chromosomes (frequency: 0.01) from individuals or families with Lynch Syndrome and was not identified in 34 control chromosomes from healthy individuals (Barrow 2010). The variant was also identified in the following databases: dbSNP (ID: rs373129248) as "With Likely benign, Uncertain significance allele", ClinVar (2x uncertain significance, 1x likely benign), and Clinvitae (1x uncertain significance, 1x likely benign). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 25 of 270130 chromosomes at a frequency of 0.00009 increasing the likelihood this could be a low frequency variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1 of 23742 chromosomes (freq: 0.00004), Latino in 1 of 34294 chromosomes (freq: 0.00003), European in 23 of 125000 chromosomes (freq: 0.0002); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.628-7C>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 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as uncertain significance.

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