Submissions for variant NM_002439.5(MSH3):c.2436-1G>A

gnomAD frequency: 0.00003  dbSNP: rs200639359

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000811107	SCV000951355	pathogenic	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 17 of the MSH3 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs200639359, gnomAD 0.005%). 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: 655023). Studies have shown that disruption of this splice site results in activation of a cryptic splice site, and produces a non-functional protein and/or introduces a premature termination codon (internal data). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV001015528	SCV001176372	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing	The c.2436-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 18 of the MSH3 gene. Alterations that disrupt the canonical splice site are expected to result in aberrant splicing. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and may result in the creation or strengthening of a novel splice acceptor site. The resulting transcripts are predicted to be either: in-frame and not expected to trigger nonsense-mediated mRNA decay (direct evidence is unavailable) or out-of-frame and trigger nonsense-mediated mRNA decay. RNA studies have demonstrated that this alteration results in an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000811107	SCV004169649	likely pathogenic	not provided	2023-04-04	criteria provided, single submitter	clinical testing	Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Not observed at significant frequency in large population cohorts (gnomAD); Observed in at least one individual participating in a prospective elective genome sequencing study (Hou et al., 2020); This variant is associated with the following publications: (PMID: 31980526, 35366121)
Myriad Genetics, Inc.	RCV003458541	SCV004189006	likely pathogenic	Familial adenomatous polyposis 4	2023-08-30	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. mRNA analysis has demonstrated abnormal mRNA splicing occurs [Myriad internal data].
Baylor Genetics	RCV003467450	SCV004197115	uncertain significance	Endometrial carcinoma	2024-02-28	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV003458541	SCV005415877	likely pathogenic	Familial adenomatous polyposis 4		criteria provided, single submitter	clinical testing	PM2_Supporting+PVS1
Fulgent Genetics, Fulgent Genetics	RCV005036187	SCV005666204	likely pathogenic	Endometrial carcinoma; Familial adenomatous polyposis 4	2024-02-18	criteria provided, single submitter	clinical testing