Submissions for variant NM_000179.3(MSH6):c.3556+1del

dbSNP: rs1064793489

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480410	SCV000566246	pathogenic	not provided	2015-04-14	criteria provided, single submitter	clinical testing	This pathogenic variant is denoted MSH6 IVS6+1delG or c.3556+1delG and consists of a deletion of one nucleotide at the +1 position of intron 6. The normal sequence, with the base that is deleted in brackets, is TCAG[g]tgag, where the capital letters are exonic and lowercase are intronic. The variant destroys a canonical splice donor 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 not, to our knowledge, been published in the literature. Based on the currently available information, we consider MSH6 c.3556+1delG to be a pathogenic variant.
Ambry Genetics	RCV000491243	SCV000580371	pathogenic	Hereditary cancer-predisposing syndrome	2022-05-26	criteria provided, single submitter	clinical testing	The c.3556+1delG intronic pathogenic mutation, located in intron 6 of the MSH6 gene, results from a deletion of one nucleotide within intron 6 of the MSH6 gene. This variant has been identified in probands whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and loss of MSH6 expression by immunohistochemistry (Ambry internal data). 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 donor site and may result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (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 a disease-causing mutation.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000586064	SCV000695872	likely pathogenic	Lynch syndrome	2016-08-11	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3556+1delG variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict loss/weakening effect on the canonical splicing donor site and ESEfinder predict changes of binding motifs for RNA splicing enhancers. However, these predictions have yet to be confirmed by functional studies. This variant is absent in 120962 control chromosomes. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as likely pathogenic.
Invitae	RCV001851149	SCV002189582	pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-02-20	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Studies have shown that disruption of this splice site alters MSH6 gene expression (PMID: 26436112). ClinVar contains an entry for this variant (Variation ID: 418872). This variant is also known as IVS6+1del. Disruption of this splice site has been observed in individual(s) with ovarian cancer (PMID: 26436112). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a splice site in intron 6 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).
Myriad Genetics, Inc.	RCV003449174	SCV004189263	likely pathogenic	Lynch syndrome 5	2023-08-24	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	RCV003463984	SCV004197561	likely pathogenic	Endometrial carcinoma	2023-10-30	criteria provided, single submitter	clinical testing