Submissions for variant NM_000179.3(MSH6):c.3172+1G>T

dbSNP: rs587779255

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074809	SCV000108020	likely pathogenic	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	Interrupts canonical donor splice site
Invitae	RCV000627710	SCV000253777	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-11-06	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 4 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 (PMID: 20487569; Invitae). ClinVar contains an entry for this variant (Variation ID: 89344). Studies have shown that disruption of this splice site results in skipping of exon 4 and/or activation of cryptic splice sites 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.
Ambry Genetics	RCV000565688	SCV000676108	pathogenic	Hereditary cancer-predisposing syndrome	2021-07-09	criteria provided, single submitter	clinical testing	The c.3172+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 4 of the MSH6 gene. This alteration was reported in a colorectal cancer patient whose tumor showed isolated loss of MSH6 by immunohistochemistry (IHC) and whose family history met Amsterdam II criteria, and in a Japanese patient diagnosed with ovarian and endometrial cancer (Talseth-Palmer BA et al. Hered. Cancer Clin. Pract. 2010 May;8:5; Hirasawa A et al. Oncotarget. 2017 Nov 28;8(68):112258-112267). This variant has also been identified in probands whose Lynch syndrome-associated tumors demonstrated isolated loss of MSH6 expression by IHC (Ambry internal data). In silico splice site analysis predicts that this alteration will weaken the native splice donor 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.
Color Diagnostics, LLC DBA Color Health	RCV000565688	SCV000903163	likely 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 4 of the MSH6 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. This variant has been reported in individuals affected with Lynch syndrome (PMID: 20487569); or ovarian and uterine cancer (PMID: 29348823). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194394	SCV001363902	pathogenic	Hereditary nonpolyposis colon cancer	2023-12-27	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3172+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: Three predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.3172+1G>T has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer, Lynch Syndrome, Ovarian and Breast Cancer(Hirasawa_2017, Talseth-Palmer_2010, Sukhanova_2022, Sjursen_2016). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 29348823, 27064304, 35655404, 20487569). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003114239	SCV003798886	pathogenic	not provided	2023-01-31	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); This variant is associated with the following publications: (PMID: 25525159, 23464690, 20487569, 29348823, 32949329, 35655404, 30202019)
Myriad Genetics, Inc.	RCV003450959	SCV004189288	likely pathogenic	Lynch syndrome 5	2023-08-22	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.
Baylor Genetics	RCV003460678	SCV004198127	pathogenic	Endometrial carcinoma	2022-10-10	criteria provided, single submitter	clinical testing