Submissions for variant NM_000179.3(MSH6):c.261-1G>C

gnomAD frequency: 0.00001  dbSNP: rs863225402

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203910	SCV000260154	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-10-05	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 1 of the MSH6 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with Lynch syndrome associated tumors (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 218055). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000222011	SCV000278641	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-23	criteria provided, single submitter	clinical testing	The c.261-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 2 of the MSH6 gene. This nucleotide position is well conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). 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 likely pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003114364	SCV003800677	likely pathogenic	Hereditary nonpolyposis colon cancer	2023-01-03	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.261-1G>C 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: Three predict the variant abolishes a 3' acceptor site. Two predict the variant strengthens a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 251470 control chromosomes. c.261-1G>C has been reported in the literature in individuals affected with Endometrial Cancer (Long_2019), Breast Cancer (Tung_2015) and Prostate Cancer (Zimmerman_2021). These data indicate that the variant may be associated with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 (n=1) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Revvity Omics, Revvity	RCV000202130	SCV003833605	likely pathogenic	not provided	2022-12-08	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003454527	SCV004189280	likely pathogenic	Lynch syndrome 5	2023-08-10	criteria provided, single submitter	clinical testing	This variant is considered likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000222011	SCV004356785	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-04-03	criteria provided, single submitter	clinical testing	This variant causes a G to C nucleotide substitution at the -1 position of intron 1 of the MSH6 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. To our knowledge, RNA studies have not been reported for this variant. This variant has not been reported in individuals affected with Lynch Syndrome in the literature, however has been reported in individuals with Lynch Syndrome in ClinVar (Variation ID: 218055). The variant has also been observed in an individual with pancreatic cancer (PMID: 33747920). 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 Likely Pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000202130	SCV000257225	pathogenic	not provided		no assertion criteria provided	clinical testing