Submissions for variant NM_000179.3(MSH6):c.4001+4_4001+8dup

dbSNP: rs587782853

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132454	SCV000187548	likely benign	Hereditary cancer-predisposing syndrome	2019-10-01	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneDx	RCV000132454	SCV000211367	benign	Hereditary cancer-predisposing syndrome	2014-09-17	criteria provided, single submitter	clinical testing	The variant is found in BR-OV-HEREDIC panel(s).
Invitae	RCV001080987	SCV000253115	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000409890	SCV000489495	likely benign	Lynch syndrome 5	2016-10-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000196451	SCV000601599	likely benign	not provided	2020-04-08	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132454	SCV000902893	likely benign	Hereditary cancer-predisposing syndrome	2016-12-13	criteria provided, single submitter	clinical testing
Mendelics	RCV000409890	SCV001135860	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000409890	SCV004019009	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 is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003488398	SCV004241761	likely benign	not specified	2023-12-29	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4001+4_4001+8dupACTAA 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. Consensus agreement among computation 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 5.1e-05 in 1600866 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in MSH6 causing Lynch Syndrome (5.1e-05 vs 0.00014), allowing no conclusion about variant significance. c.4001+4_4001+8dupACTAA has been reported in the literature at-least one hereditary cancer sample (example: Watson_2013). This report does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 24307375). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000196451	SCV000592667	uncertain significance	not provided		no assertion criteria provided	clinical testing	The MSH6 c.4001+4_4001+8dup variant was identified in 1 of 256 proband chromosomes (frequency: 0.004) from individuals or families with hereditary cancer (Watson 2013). The variant was also identified in dbSNP (ID: rs781320845) as “other”, Clinvitae database (conflicting interpretations of pathogenicity), ClinVar database (as uncertain significance by Ambry Genetics, likely benign by Invitae, benign by GeneDx) and UMD (1x with an “unclassified variant” classification). The variant was not identified in GeneInsight - COGR database, InSiGHT Colon Cancer Gene Variant Database (LOVD), Zhejiang Colon Cancer Database (LOVD), “Mismatch Repair Genes Variant Database”, “MMR Gene Unclassified Variants Database” . The variant was identified in the Exome Aggregation Consortium database (August 8, 2016) in 4 of 111884 chromosomes (freq. 3.58x10-5) in the following populations: European (Non-Finnish) in 4 of 61054 but was not seen in African, East Asian, Finnish, Latino, Other or South Asian populations. In addition this variant was identified in case in our laboratory as co-occurring with a pathogenic MLH1 p.Lys751SerfsX3 variant, increasing the likelihood that it does not have clinical significance. The c.4001+4_4001+8dup variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. However, 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.