Submissions for variant NM_000179.3(MSH6):c.3802-3A>G

dbSNP: rs778499259

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001179951	SCV001344756	uncertain significance	Hereditary cancer-predisposing syndrome	2019-12-09	criteria provided, single submitter	clinical testing	This variant causes an A>G nucleotide substitution at the -3 position of intron 8 of the MSH6 gene. Splice site prediction tools are inconclusive regarding the impact of this variant on RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/250996 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001875961	SCV002122460	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change falls in intron 8 of the MSH6 gene. It does not directly change the encoded amino acid sequence of the MSH6 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs778499259, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 920897). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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 available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sema4, Sema4	RCV001179951	SCV002528072	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-02	criteria provided, single submitter	curation
Ambry Genetics	RCV001179951	SCV002620165	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-26	criteria provided, single submitter	clinical testing	The c.3802-3A>G intronic variant results from an A to G substitution 3 nucleotides upstream from coding exon 9 in the MSH6 gene. This nucleotide position is conserved on limited sequence alignment. In silico splice site analysis predicts that this alteration may result in the creation or strengthening of a novel splice acceptor site; however, direct evidence is insufficient at this time (Ambry internal data). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.