Submissions for variant NM_000179.2(MSH6):c.4001+11_4001+15dup (rs587779302)

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160733	SCV000211369	benign	Hereditary cancer-predisposing syndrome	2014-10-01	criteria provided, single submitter	clinical testing	The variant is found in BR-OV-HEREDIC,HEREDICANCER panel(s).
Invitae	RCV000587529	SCV000253114	likely benign	not provided	2015-05-15	criteria provided, single submitter	clinical testing
Illumina Clinical Services Laboratory,Illumina	RCV000074967	SCV000430981	uncertain significance	Lynch syndrome	2016-06-14	criteria provided, single submitter	clinical testing
Color Health, Inc	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	Hereditary nonpolyposis colorectal cancer type 5	2018-02-02	criteria provided, single submitter	clinical testing
Mendelics	RCV000074967	SCV000837930	uncertain significance	Lynch syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Invitae	RCV001463861	SCV001667811	likely benign	Hereditary nonpolyposis colorectal neoplasms	2015-10-30	criteria provided, single submitter	clinical testing
GeneDx	RCV000587529	SCV001861252	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
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.