Submissions for variant NM_002439.5(MSH3):c.1341-1G>T

gnomAD frequency: 0.00004  dbSNP: rs61754780

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000803244	SCV000943106	likely pathogenic	not provided	2024-06-04	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 8 of the MSH3 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 present in population databases (rs61754780, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 648498). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
Ambry Genetics	RCV001010949	SCV001171214	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-03-29	criteria provided, single submitter	clinical testing	The c.1341-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 9 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 acceptor site and will 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). 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.
Department of Pediatrics, Memorial Sloan Kettering Cancer Center	RCV001523828	SCV001478127	likely pathogenic	Familial adenomatous polyposis 4	2020-12-15	criteria provided, single submitter	research
GeneDx	RCV000803244	SCV002526586	uncertain significance	not provided	2022-04-13	criteria provided, single submitter	clinical testing	Observed in the heterozygous state in individuals with retinoblastoma (Francis 2021, Salo-Mullen 2021); 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; This variant is associated with the following publications: (PMID: 33466343, 34250384, 34308366)
Sema4, Sema4	RCV001010949	SCV002535944	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-03-13	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV001523828	SCV004189011	likely pathogenic	Familial adenomatous polyposis 4	2023-08-29	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	RCV003461143	SCV004195179	likely pathogenic	Endometrial carcinoma	2024-01-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000803244	SCV005623869	likely pathogenic	not provided	2024-06-26	criteria provided, single submitter	clinical testing	The MSH3 c.1341-1G>T variant disrupts a canonical splice-acceptor site and is predicted to interfere with normal MSH3 mRNA splicing. This variant has not been reported in individuals with MSH3-related conditions in the published literature. However, it was reported in a boy affected with retinoblastoma (PMIDs: 33466343 (2021), 34308366 (2021)). The frequency of this variant in the general population, 0.00029 (9/30584 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. A study using paired DNA and RNA patient samples also observed the variant to have a deleterious effect on splicing (PMID: 36563937 (2023)). Based on the available information, this variant is classified as likely pathogenic.