ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.4001+2TAAC[4] (rs267608132)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160734 SCV000186783 likely benign Hereditary cancer-predisposing syndrome 2013-03-21 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.
GeneDx RCV000204092 SCV000211370 benign not provided 2015-03-03 criteria provided, single submitter clinical testing
Invitae RCV000204092 SCV000262244 likely benign not provided 2016-03-01 criteria provided, single submitter clinical testing
Counsyl RCV000409636 SCV000489203 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-09-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160734 SCV000685476 likely benign Hereditary cancer-predisposing syndrome 2014-12-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780481 SCV000917766 benign not specified 2018-06-07 criteria provided, single submitter clinical testing Variant summary: MSH6 c.4001+12_4001+15dupACTA alters a nucleotide located in the intronic region that is not widely known to affect splicing. 5/5 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 0.00028 in 270198 control chromosomes. The observed variant frequency is approximately 2 fold above 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. To our knowledge, no occurrence of c.4001+12_4001+15dupACTA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics RCV000409636 SCV001135858 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV001439800 SCV001642694 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-08 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001357088 SCV001552434 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The MSH6 c.4001+12_4001+15dupACTA variant was identified in 1 of 1500 proband chromosomes (frequency: 0.00066) from individuals or families with CRC and was identified as non-pathogenic variant (Woods 2010). The variant was also identified in dbSNP (ID: rs587782538) as “With other allele”, ClinVar (4x, as benign by GeneDx, as likely benign by Ambry, Invitae and Counsyl), Clinvitae (3x, as likely benign), Insight Colon Cancer Gene Variant Database (3x, as Class 3), Insight Hereditary Tumors Database (3x), databases. The variant was not identified in GeneInsight-COGR, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was identified in control databases in 75 of 270198 chromosomes at a frequency of 0.00028 in the following populations: African in 17 of 23654 chromosomes (freq. 0.0007), Latino in 13 of 34140 chromosomes (freq. 0.00038), European in 35 of 123578 chromosomes (freq. 0.00028), East Asian in 5 of 1860 chromosomes (freq. 0.00026), and other in 1 of 6346 chromosomes (freq. 0.00015), Ashkenazi Jewish in 1 of 10042 chromosomes (freq. 0.0001), South Asian in 3 of 30528 chromosomes (freq. 0.0001), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. A co-occurring pathogenic BRCA1 variant (c.709G>T, p.Glu237X) is identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that c.4001+12_4001+15dupACTA variant does not have clinical significance 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000204092 SCV001742143 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000204092 SCV001809143 likely benign not provided no assertion criteria provided clinical testing

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