Submissions for variant NM_000179.3(MSH6):c.3647-6T>A

gnomAD frequency: 0.00134  dbSNP: rs182871847

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115418	SCV000149327	likely benign	not specified	2017-09-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae	RCV001081821	SCV000252629	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000115418	SCV000595843	likely benign	not specified	2019-07-12	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115418	SCV000601581	benign	not specified	2021-08-25	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000579665	SCV000685425	likely benign	Hereditary cancer-predisposing syndrome	2015-04-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587059	SCV000695881	benign	not provided	2016-10-06	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.3647-6T>A variant involves the alteration of a non-conserved intronic nucleotide with 4/5 splice prediction tools predict no significant impact on normal splicing, which a reputable database reports in vitro and ex vivo analyses that support these predictions. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 47/120200 (1/2557), predominantly in the African cohort, 42/10262 (1/244), which exceeds the estimated maximal expected allele frequency for a pathogenic MSH6 variant of 1/7037. Therefore, suggesting this is likely a benign polymorphism found primarily in population(s) of African origin. The variant of interest has been reported by multiple clinical diagnostic laboratories/databases with conflicting classifications "Benign/Likely Benign/Uncertain Significance." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.
Counsyl	RCV000662552	SCV000785135	likely benign	Lynch syndrome 5	2017-05-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000662552	SCV001299976	uncertain significance	Lynch syndrome 5	2019-10-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Sema4, Sema4	RCV000579665	SCV002528053	benign	Hereditary cancer-predisposing syndrome	2020-10-23	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000115418	SCV002552354	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662552	SCV004018992	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is intronic and is not expected to impact mRNA splicing. This variant has been observed at a population frequency that is significantly greater than expected given the associated disease prevalence and penetrance. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000587059	SCV004563437	likely benign	not provided	2023-08-17	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997250	SCV004819841	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000579665	SCV005045356	benign	Hereditary cancer-predisposing syndrome	2024-04-09	criteria provided, single submitter	clinical testing
True Health Diagnostics	RCV000579665	SCV000788051	uncertain significance	Hereditary cancer-predisposing syndrome	2018-02-20	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357466	SCV001552947	likely benign	Endometrial carcinoma		no assertion criteria provided	clinical testing	The MSH6 c.3647-6T>A variant was not identified in the literature. The variant was identified in dbSNP (ID: rs182871847) as "With Likely benign, other allele", ClinVar (classified as benign by Invitae and two clinical laboratories; as likely benign by GeneDx, Color and Councyl; as uncertain significance by two submitters), and in UMD-LSDB (1x as likely neutral). The variant was identified in control databases in 117 of 276924 chromosomes at a frequency of 0.0004 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 107 of 24034 chromosomes (freq: 0.005), Other in 1 of 6444 chromosomes (freq: 0.0002), Latino in 9 of 34364 chromosomes (freq: 0.0003), while the variant was not observed in the European, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The c.3647-6T>A 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 addition, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% 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.