Total submissions: 19
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
International Society for Gastrointestinal Hereditary Tumours |
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 | 2024-10-18 | criteria provided, single submitter | clinical testing | The c.3439-2A>G intronic variant results from a A to G substitution two nucleotides before coding exon 6 of the MSH6 gene. 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. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in a proband(s) who met Amsterdam I/II criteria for Lynch syndrome and/or whose tumor(s) demonstrated loss of MSH6 expression by immunohistochemistry (Kolodner, 1999; Ambry internal data). 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, 2015; Long, 2019). This nucleotide position is highly conserved in available vertebrate species. RNA studies have demonstrated this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). 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, 1999). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Based on the available evidence, this alteration is classified as pathogenic. |
Labcorp Genetics |
RCV000524176 | SCV000253678 | pathogenic | Hereditary nonpolyposis colorectal neoplasms | 2024-01-31 | criteria provided, single submitter | clinical testing | This sequence change affects an acceptor splice site in intron 5 of the MSH6 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with clinical features of Lynch syndrome (PMID: 10537275, 20028993, 25980754; Invitae). This variant is also known as IVS5-2A>G. ClinVar contains an entry for this variant (Variation ID: 89391). Studies have shown that disruption of this splice site results in exon 6 skipping and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. |
Mayo Clinic Laboratories, |
RCV000202159 | SCV000257254 | pathogenic | not provided | 2024-02-28 | criteria provided, single submitter | clinical testing | PP5, PM2_moderate, PVS1 |
Laboratory for Molecular Medicine, |
RCV000074859 | SCV000271401 | pathogenic | Lynch syndrome | 2021-10-27 | criteria provided, single submitter | clinical testing | The c.3439-2A>G variant in MSH6 has been reported in 4 individuals with MSH6-associated cancers (Kolodner 1999 PMID: 10537275, Baglietto 2010 PMID: 20028993, , Long 2019 PMID: 30612635) and in 1 individual undergoing clinical genetic testing for Lynch Syndrome (Yurgelun 2015 PMID: 25980754) . It was absent from large population studies. This variant occurs within the canonical splice site (+/- 1,2) and is predicted to cause altered splicing leading to an abnormal or absent protein. This was corroborated by a functional study using patient RNA that shows that this variant causes out-of-frame skipping of exon 6 (Thompson 2013 PMID: 22949379). Loss of function of the MSH6 gene is an established disease mechanism in autosomal dominant Lynch syndrome. In addition, this variant was classified as Likely Pathogenic on June 21, 2019 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000108071.2). In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Lynch syndrome. ACMG/AMP Criteria applied: PVS1, PS3_Supporting, PM2_Supporting, PS4_Supporting. |
Gene |
RCV000202159 | SCV000279108 | pathogenic | not provided | 2023-05-19 | criteria provided, single submitter | clinical testing | Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; This variant is associated with the following publications: (PMID: 10537275, 31447099, 20028993, 25980754, 28152038, 28514183, 18269114, 26866578, 22949387, 25561518, 30612635, 32719484, 34308104, 28888541) |
Color Diagnostics, |
RCV000130487 | SCV000537629 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-01-18 | 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. An RNA 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
ARUP Laboratories, |
RCV000202159 | SCV000604276 | pathogenic | not provided | 2023-11-27 | criteria provided, single submitter | clinical testing | The MSH6 c.3439-2A>G variant (rs267608098), also known as IVS5-2A>G, has been described in the literature in individuals with colorectal cancer and families with Lynch syndrome (Baglietto 2010, Kolodner 1999, South 2009, Yurgelun 2015). It is reported as pathogenic by several laboratories in ClinVar (Variation ID: 89391) and is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. This variant abolishes the canonical splice acceptor site of intron 5, which is likely to disrupt gene function. Based on available information, this variant is considered pathogenic. References: Baglietto L et al. Risks of Lynch syndrome cancers for MSH6 mutation carriers. J Natl Cancer Inst. 2010;102(3):193-201. PMID: 20028993. Kolodner RD et al. Germ-line msh6 mutations in colorectal cancer families. Cancer Res. 1999;59(20):5068-74. PMID: 10537275. South CD et al. Immunohistochemistry staining for the mismatch repair proteins in the clinical care of patients with colorectal cancer. Genet Med. 2009;11(11):812-7. PMID: 19752738. Yurgelun MB et al. Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome. Gastroenterology. 2015 Sep;149(3):604-13.e20. PMID: 25980754. |
Counsyl | RCV000576575 | SCV000677748 | likely pathogenic | Lynch syndrome 5 | 2017-01-04 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
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 | 2023-01-20 | criteria provided, single submitter | clinical testing | This variant disrupts a canonical splice-acceptor site and interferes with normal MSH6 mRNA splicing. It has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals with Lynch syndrome or colorectal cancer (PMIDs: 25980754 (2015), 10537275 (1999)), endometrial cancer (PMIDs: 30612635 (2019), 29345684 (2018)), breast/ovarian cancer (PMID: 30128536 (2018)), and acute lymphoblastic leukemia (PMID: 34308104 (2021)). The variant also showed deleterious effects on protein function in a yeast-based complementation assay (PMID: 10537275 (1999)). Based on the available information, this variant is classified as pathogenic. |
Baylor Genetics | RCV001292865 | SCV001481549 | pathogenic | Endometrial carcinoma | 2024-02-15 | criteria provided, single submitter | clinical testing | |
CHEO Genetics Diagnostic Laboratory, |
RCV001798254 | SCV002042052 | pathogenic | Breast and/or ovarian cancer | 2019-08-28 | criteria provided, single submitter | clinical testing | |
Sema4, |
RCV000130487 | SCV002528028 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-11-16 | criteria provided, single submitter | curation | |
Revvity Omics, |
RCV000202159 | SCV003820234 | pathogenic | not provided | 2022-11-10 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV000576575 | SCV004018971 | pathogenic | Lynch syndrome 5 | 2023-03-29 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant is strongly associated with more severe personal and family histories of cancer, typical for individuals with pathogenic variants in this gene [PMID: 25085752]. |
All of Us Research Program, |
RCV000074859 | SCV004822616 | pathogenic | Lynch syndrome | 2024-04-25 | 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. An RNA functional study using RNA derived from a carrier individual has reported that this variant causes out-of-frame skipping of exon 6 (PMID: 22949379). The variant has been reported to have a splicing impact by external laboratories (ClinVar: SCV000253678.11, SCV000185356.9). 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 (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. |
Department of Pathology and Laboratory Medicine, |
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. | |
Prevention |
RCV004739335 | SCV005362767 | pathogenic | MSH6-related disorder | 2024-08-12 | no assertion criteria provided | clinical testing | The MSH6 c.3439-2A>G variant is predicted to disrupt the AG splice acceptor site and interfere with normal splicing. This variant has been reported in multiple individuals with Lynch syndrome cancers (Table 3 - IVS5-2A>G - Kolodner et al. 1999. PubMed ID: 10537275; Baglietto et al. 2010. PubMed ID: 20028993; Yurgelun et al. 2015. PubMed ID: 25980754). This variant is not present in the gnomAD population database and has been interpreted by multiple labs as likely pathogenic/pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/89391/). Variants that disrupt the consensus splice acceptor site in MSH6 are expected to be pathogenic. This variant is interpreted as pathogenic. |