ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3439-2A>G (rs267608098)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074859 SCV000108071 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000130487 SCV000185356 pathogenic Hereditary cancer-predisposing syndrome 2019-11-27 criteria provided, single submitter clinical testing The c.3439-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides before coding exon 6 of the MSH6 gene. This mutation was reported in a proband diagnosed with colorectal cancer at age 69, whose father and paternal grandfather were also diagnosed with colorectal cancer (at ages 48 and 70, respectively). This alteration was predicted to cause skipping of coding exon 6, and a deletion of this region in yeast resulted in complete loss of MSH6 function (Kolodner RD et al. Cancer Res. 1999 Oct;59:5068-74). This mutation was also identified in two additional patients with a history of Lynch/HNPCC-associated cancers and/or polyps and was reported in a cohort of patients diagnosed with endometrial cancer or complex atypical hyperplasia (Yurgelun MB et al. Gastroenterology. 2015 Sep;149:604-13.e20;Long B et al. Gynecol. Oncol., 2019 01;152:20-25). RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic.
Invitae RCV000524176 SCV000253678 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-10-19 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals and families affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 10537275, 20028993, 25980754, Invitae). This variant is also known as IVS5-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 89391). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000074859 SCV000271401 pathogenic Lynch syndrome 2016-03-29 criteria provided, single submitter clinical testing The c.3439-2A>G variant in MSH6 has been reported in 3 individuals with MSH6-ass ociated cancers (Kolodner 1999, Baglietto 2010) and was absent from large popula tion studies. This variant occurs in the invariant region (- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abno rmal or absent protein. Heterozygous loss-of-function of the MSH6 gene is an est ablished disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as Likely Pathogenic on September 5, 2013 by the ClinGen -approved InSiGHT expert panel (ClinVar SCV000108071.2). In summary, this varian t meets criteria to be classified as pathogenic for Lynch syndrome in an autosom al dominant manner based upon predicted impact to the protein, reports in multip le affected individuals and absence in controls.
GeneDx RCV000202159 SCV000279108 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.3439-2A>G or IVS5-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 5 of the MSH6 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. MSH6 c.3439-2A>G has been observed in individuals with personal and/or family history of Lynch-associated cancers and/or polyps and was found to cause loss of mismatch repair function (Kolodner 1999, Baglietto 2010, Yurgelun 2015, Haraldsdottir 2016). We consider this variant to be pathogenic.
Color Health, Inc RCV000130487 SCV000537629 pathogenic Hereditary cancer-predisposing syndrome 2020-10-27 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 5 of the MSH6 gene. A functional study using RNA derived from a carrier individual has reported that this variant causes out-of-frame skipping of exon 6 (PMID: 22949379). This variant is expected to result in an absent or non-functional protein product. This variant has been observed in individuals affected with or suspected of having Lynch syndrome (PMID: 10537275, 25980754), colorectal cancer (PMID: 20028993), endometrial cancer (PMID: 29345684, 30612635), ovarian cancer (PMID: 30128536), and breast cancer (PMID: 30128536). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of MSH6 function is a known mechanism of disease ( Based on the available evidence, this variant is classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000508266 SCV000604276 pathogenic not specified 2016-12-13 criteria provided, single submitter clinical testing
Counsyl RCV000576575 SCV000677748 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-01-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001526853 SCV000695866 pathogenic Hereditary nonpolyposis colon cancer 2021-05-19 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3439-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 3 prime acceptor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Kolodner_1999). The variant was absent in 251432 control chromosomes (gnomAD). c.3439-2A>G has been reported in the literature in individuals affected with Lynch Syndrome (e.g. Kolodner_1999, Baglietto_2010, Yurgelun_2015). These data indicate that the variant is likely to be associated with disease. Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202159 SCV000888274 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV001292865 SCV001481549 pathogenic Endometrial carcinoma 2020-07-03 criteria provided, single submitter clinical testing This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Mayo Clinic Laboratories, Mayo Clinic RCV000202159 SCV000257254 pathogenic not provided 2018-02-23 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353640 SCV000592642 pathogenic Carcinoma of colon no assertion criteria provided clinical testing The MSH6 c.3439-2A>G variant was identified in 3 of 3026 proband chromosomes (frequency: 0.001) from individuals or families with Lynch Syndrome (Kolodner 1999, Biaglietto 2009, Yurgelun 2015). The variant was identified in dbSNP (rs267608098) as “with likely pathogenic, pathogenic allele” and ClinVar (interpreted as "pathogenic" by Invitae and 8 others and "likely pathogenic" by 3 laboratories). The variant was not identified in UMD-LSDB. The variant was not identified in the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The c.3439-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predicted a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic.

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