Submissions for variant NM_000179.3(MSH6):c.628-8C>T

gnomAD frequency: 0.00002  dbSNP: rs767991179

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000228163	SCV000283851	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-10-20	criteria provided, single submitter	clinical testing
GeneDx	RCV001722209	SCV000522507	likely benign	not provided	2019-02-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV001184776	SCV001350841	likely benign	Hereditary cancer-predisposing syndrome	2019-06-26	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001184776	SCV002536336	likely benign	Hereditary cancer-predisposing syndrome	2021-11-23	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001722209	SCV004222050	likely benign	not provided	2023-09-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357663	SCV001553192	uncertain significance	Carcinoma of colon		no assertion criteria provided	clinical testing	The MSH6 c.628-8C>T, r.(spl?) variant was not identified in the literature nor was it identified in the GeneInsight-COGR, COSMIC, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, or Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs767991179) as “With Likely benign allele”, and in ClinVar and Clinvitae databases (2x classified as likely benign by Invitae and GeneDx). The variant was identified in control databases in 4 of 238952 chromosomes at a frequency of 0.00002 in the following populations: South Asian in 3 of 30704 chromosomes (freq. 0.0001); European non-Finnish in 1 of 109948 chromosomes (freq. 0.000009) increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The c.628-8C>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. However, only 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.