Submissions for variant NM_000179.3(MSH6):c.3173-10C>T

gnomAD frequency: 0.00003  dbSNP: rs587780559

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000119240	SCV000153987	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000129377	SCV000184142	uncertain significance	Hereditary cancer-predisposing syndrome	2014-03-18	criteria provided, single submitter	clinical testing	​The c.3173-10C>T intronic variant results from a C to T substitution ten nucleotides before coding exon 5 in the MSH6 gene. This variant was not reported in population-based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project. To date, this alteration has been detected with an allele frequency of approximately 0.006% (greater than 17,000 alleles tested) in our clinical cohort (includes this individual). Based on nucleotide sequence alignment, this position is poorly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of c.3173-10C>T remains unclear.
GeneDx	RCV001357336	SCV000513697	likely benign	not provided	2021-04-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129377	SCV000908411	likely benign	Hereditary cancer-predisposing syndrome	2017-08-14	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000433737	SCV000917785	uncertain significance	not specified	2019-07-26	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3173-10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251330 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3173-10C>T in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV003997308	SCV004826080	likely benign	Lynch syndrome	2023-09-17	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357336	SCV001552780	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 c.3173-10C>T variant was identified in 1 of 976 proband chromosomes (frequency: 0.001) from an individual with breast cancer (Tung 2016). The variant was also identified in the following databases: dbSNP (ID: rs587780559) as "With Likely benign, Uncertain significance allele", ClinVar (2x likely benign, 1x uncertain significance), and Clinvitae (2x likely benign, 1x uncertain significance). The variant was not identified in Cosmic, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or the Insight Hereditary Tumors Database. The variant was identified in control databases in 2 of 277084 chromosomes at a frequency of 0.000007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include European in 2 of 126616 chromosomes (freq: 0.00002), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The c.3173-10C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. In silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.