Submissions for variant NM_000179.3(MSH6):c.3647-3C>T

dbSNP: rs1553332959

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000573671	SCV000662467	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-20	criteria provided, single submitter	clinical testing	The c.3647-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 8 in the MSH6 gene. This nucleotide position is not well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001049439	SCV001213488	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-10	criteria provided, single submitter	clinical testing	This sequence change falls in intron 7 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 not present in population databases (gnomAD no frequency). 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: 479903). 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 is not likely to affect RNA splicing. 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.
Illumina Laboratory Services, Illumina	RCV001139790	SCV001299977	uncertain significance	Lynch syndrome 5	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
All of Us Research Program, National Institutes of Health	RCV004000874	SCV004824821	uncertain significance	Lynch syndrome	2023-05-04	criteria provided, single submitter	clinical testing	This variant causes a C to T nucleotide substitution at the -3 position of intron 7 of the MSH6 gene. To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has not been identified 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.