Submissions for variant NM_002439.5(MSH3):c.1568+1G>C

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002405562	SCV002709958	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-07-20	criteria provided, single submitter	clinical testing	The c.1568+1G>C intronic variant results from a G to C substitution one nucleotide after coding exon 10 of the MSH3 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor 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.
Myriad Genetics, Inc.	RCV003458861	SCV004189046	likely pathogenic	Familial adenomatous polyposis 4	2023-08-03	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003774388	SCV004628363	likely pathogenic	not provided	2023-07-14	criteria provided, single submitter	clinical testing	Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 1775409). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 10 of the MSH3 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 MSH3 are known to be pathogenic (PMID: 27476653).