Submissions for variant NM_000179.3(MSH6):c.628-13C>G

dbSNP: rs538280815

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000584305	SCV000690461	likely benign	Hereditary cancer-predisposing syndrome	2016-05-22	criteria provided, single submitter	clinical testing
GeneDx	RCV001712596	SCV000716132	likely benign	not provided	2021-11-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001142202	SCV001302615	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.
Invitae	RCV002061863	SCV002407234	benign	Hereditary nonpolyposis colorectal neoplasms	2023-09-30	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000584305	SCV002536334	likely benign	Hereditary cancer-predisposing syndrome	2021-11-29	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV004002356	SCV004815069	likely benign	Lynch syndrome	2023-03-04	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357031	SCV001552356	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 c.628-13C>G variant was not identified in the literature nor was it identified in the GeneInsight-COGR, Cosmic, UMD-LSDB, Zhejiang University, Mismatch Repair Genes Variant Database, MMR Gene Unclassified Variants Database, or Insight Hereditary Tumors databases. The variant was identified in dbSNP (ID: rs538280815), ClinVar (classified as likely benign by Color Genomics and GeneDx), and Clinvitae databases. The variant was identified in control databases in 25 of 237946 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was identified in South Asian population in 25 of 30692 chromosomes (freq: 0.001), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, East Asian, or Finnish populations. The variant occurs outside of the splicing consensus sequence and 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.