Submissions for variant NM_000179.3(MSH6):c.4001+11_4001+15dup

gnomAD frequency: 0.00019  dbSNP: rs587779302

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000074967	SCV000430981	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160733	SCV000690426	likely benign	Hereditary cancer-predisposing syndrome	2016-02-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587529	SCV000695907	benign	not provided	2016-12-01	criteria provided, single submitter	clinical testing	Variant summary: The MSH6 c.4001+11_4001+15dupAACTA variant results into duplication of five non-conserved nucleotides in intron 9 at a region not widely known to involve in splicing. Mutation taster predicts a benign outcome for this variant. In addition, 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 29/111750 control chromosomes from ExAC at a frequency of 0.0002595, which is approximately 2 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories have classified this variant as likely benign/benign. The variant of interest has not, to our knowledge, been reported in affected individuals in literature. Taken together, this variant is classified as Benign.
Counsyl	RCV000663009	SCV000786021	likely benign	Lynch syndrome 5	2018-02-02	criteria provided, single submitter	clinical testing
Mendelics	RCV003323284	SCV000837930	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
Invitae	RCV001463861	SCV001667811	likely benign	Hereditary nonpolyposis colorectal neoplasms	2021-12-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000587529	SCV001861252	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000160733	SCV002626226	likely benign	Hereditary cancer-predisposing syndrome	2014-11-06	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003320554	SCV004024820	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
GeneDx	RCV000160733	SCV000211369	benign	Hereditary cancer-predisposing syndrome	2014-10-01	flagged submission	clinical testing	The variant is found in BR-OV-HEREDIC,HEREDICANCER panel(s).
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000074967	SCV001550041	likely benign	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 c.4001+11_4001+15dup variant was not identified in the literature nor was it identified in the UMD-LSDB database. The variant was identified in dbSNP (ID: rs730882138) as "With Likely benign, other allele" and ClinVar (classified as likely benign by Invitae, Counsyl and two other submitters). The variant was identified in control databases in 70 of 269486 chromosomes at a frequency of 0.0003, 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: South Asian in 23 of 30492 chromosomes (freq: 0.0008), European in 41 of 123358 chromosomes (freq: 0.0003), East Asian in 3 of 18612 chromosomes (freq: 0.0002), and Finnish in 3 of 23088 chromosomes (freq: 0.0001), while the variant was not observed in the African, Ashkenazi Jewish, Latino, or Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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.
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000160733	SCV002050295	likely benign	Hereditary cancer-predisposing syndrome	2021-12-21	no assertion criteria provided	clinical testing