Submissions for variant NM_000179.3(MSH6):c.3439-1G>T

dbSNP: rs587779263

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074858	SCV000108070	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
GeneDx	RCV000215652	SCV000279241	pathogenic	not provided	2016-03-03	criteria provided, single submitter	clinical testing	This variant is denoted MSH6 c.3439-1G>T or IVS5-1G>T and consists of a G>T nucleotide substitution at the -1 position of intron 5 of the MSH6 gene. This 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. This variant has been reported in an individual with colorectal cancer from a large kindred affected by colorectal and other Lynch-related cancers whose tumor demonstrated loss of MSH6 protein expression (Talseth-Palmer 2010). MSH6 c.3439-1G>T has also been reported in another individual with a personal and family history of colorectal cancer as well as a patient with prostate cancer whose family history met Amsterdam criteria (Rosty 2014, Chubb 2015). While the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as likely pathogenic (Thompson 2014), this classification did not take into account evidence from any of these literature reports. Based on currently available information, we consider MSH6 c.3439-1G>T to be pathogenic.
Ambry Genetics	RCV000491481	SCV000580140	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-28	criteria provided, single submitter	clinical testing	The c.3439-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide before coding exon 6 of the MSH6 gene. This mutation has been reported in individuals with early onset colon cancer and suspected Lynch syndrome (Chubb D et al. J. Clin. Oncol. 2015 Feb;33:426-32; Cruz-Correa M et al. Fam. Cancer 2015 Sep;14:415-25). In one family fulfilling Amsterdam II criteria, the proband was diagnosed with colorectal cancer at 54 that demonstrated loss of MSH6 protein by immunohistochemistry; other cancers in the family included colon, ovarian, and endometrial (Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5). This variant has also been identified in several individuals whose Lynch syndrome associated tumors demonstrated isolated loss of MSH6 on immunohistochemistry (IHC) (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. RNA studies have demonstrated that 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 a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000215652	SCV000601573	pathogenic	not provided	2016-09-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000491481	SCV000690355	pathogenic	Hereditary cancer-predisposing syndrome	2021-12-13	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the -1 position of intron 5 of the MSH6 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. Although this prediction has not been confirmed in published RNA studies, this variant is expected to result in an absent or disrupted protein product. This variant has been observed in individuals and families affected with Lynch syndrome-associated cancer (PMID: 20487569, 25782445, 27064304, 27329137) and an individual from a colon cancer family registry affected with prostate cancer (PMID: 25117503). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000074858	SCV000695865	pathogenic	Lynch syndrome	2019-03-12	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3439-1G>T 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 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 246190 control chromosomes (gnomAD). This variant has been reported in the literature in individuals affected with Lynch syndrome and Prostate cancer (Talseth-Palmer_2010, Rosty_2014, Chubb_2015, Sjursen_2016, Chubb_2016). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae	RCV000629776	SCV000750732	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-09	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 Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 5559809, 10537275, 20028993, 20487569, 25980754; Invitae). ClinVar contains an entry for this variant (Variation ID: 89390). Studies have shown that disruption of this splice site results in skipping of exon 6 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.
Genetics and Molecular Pathology, SA Pathology	RCV002272051	SCV002556838	likely pathogenic	Lynch syndrome 1	2020-05-14	criteria provided, single submitter	clinical testing	The MSH6 c.3439-1G>T variant has been classified as Likely Pathogenic, largely based on InSiGHT's classification. (PVS1, PM2) The MSH6 c.3439-1G>T variant is located at the splice acceptor site. Computational predictions support a deleterious effect on splicing and a likely disruption of the protein reading frame and non-sense mediated decay of the resulting protein product (PVS1). This variant is absent from population databases (PM2). The variant has been reported in dbSNP (rs587779263) and has been reported as Likely pathogenic by other diagnostic laboratories (ClinVar Variation ID: 89390).
Fulgent Genetics, Fulgent Genetics	RCV002483121	SCV002790454	pathogenic	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-11-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003450968	SCV004187418	pathogenic	Lynch syndrome 5	2023-08-23	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: 27363726].
Baylor Genetics	RCV003460684	SCV004195798	pathogenic	Endometrial carcinoma	2023-05-07	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000215652	SCV000592643	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000215652	SCV001951686	pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000215652	SCV001970754	pathogenic	not provided		no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV003483460	SCV004228957	not provided	Hereditary nonpolyposis colon cancer		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 07-27-2015 by Lab Myriad. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.