Submissions for variant NM_000179.3(MSH6):c.4001+2TAAC[2]

dbSNP: rs267608132

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074968	SCV000108184	likely benign	Lynch syndrome	2019-06-21	reviewed by expert panel	curation	No effect on splicing in minigene & RT-PCR assay
Ambry Genetics	RCV000160732	SCV000187066	likely benign	Hereditary cancer-predisposing syndrome	2018-01-04	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	RCV000160732	SCV000211368	benign	Hereditary cancer-predisposing syndrome	2014-08-19	criteria provided, single submitter	clinical testing	The variant is found in HEREDICANCER,COLO-HEREDIC panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV001079571	SCV000262471	benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-03	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000202155	SCV000339455	benign	not specified	2016-02-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000412187	SCV000489228	likely benign	Lynch syndrome 5	2016-09-06	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202155	SCV000595844	likely benign	not specified	2019-03-04	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202155	SCV000601598	likely benign	not specified	2016-12-20	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160732	SCV000690428	likely benign	Hereditary cancer-predisposing syndrome	2015-02-13	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656542	SCV000805901	likely benign	not provided	2017-08-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000202155	SCV000919767	benign	not specified	2018-04-30	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4001+12_4001+15delACTA variant results in 4 intronic nucleotides deletion, with 5/5 computational tools predicting 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 0.0012 in 270798 control chromosomes (gnomAD). The observed variant frequency is approximately 8.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), strongly suggesting that the variant is benign. The variant, c.4001+12_4001+15delACTA, has been reported in the literature in individuals affected with Lynch Syndrome but also in unaffected controls and was classified as a polymorphism (Peterlongo_2003, Naruse_2009). In addition, the variant was detected in a patient with the pathogenic MSH2 variant c.211+1G>C that was shown to cause aberrant splicing (Naruse_2009). Since the penetrance of Lynch Syndrome (0.67) due to this variant appears to be lower than expected (0.8), no conclusions can be drawn from these data. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and the majority classified the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000412187	SCV001135859	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV001030564	SCV001193654	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000656542	SCV001501274	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	MSH6: BS1
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000656542	SCV002010080	likely benign	not provided	2021-11-03	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798255	SCV002042056	likely benign	Breast and/or ovarian cancer	2023-04-05	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202155	SCV002552375	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002477213	SCV002803142	likely benign	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-07-28	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000160732	SCV004228069	benign	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000656542	SCV004563327	likely benign	not provided	2023-01-06	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000656542	SCV000257294	likely benign	not provided	2017-11-10	no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000412187	SCV000745655	likely benign	Lynch syndrome 5	2016-04-29	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000160732	SCV000788055	likely benign	Hereditary cancer-predisposing syndrome	2017-08-11	no assertion criteria provided	clinical testing
Ding PR Lab, Sun Yat-sen University Cancer Center	RCV001093682	SCV001250863	uncertain significance	Lynch syndrome 1		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355407	SCV001550287	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MSH6 c.4001+12_4001+15dupACTA variant was identified in 1 of 1500 proband chromosomes (frequency: 0.0007) from individuals or families with CRC and was identified as a non-pathogenic variant (Woods 2010). The variant was also identified in dbSNP (ID: rs587782538) as “With other allele”, ClinVar (4x, as benign by GeneDx, as likely benign by Ambry, Invitae and Counsyl), Clinvitae (3x, as likely benign), and the Insight Colon Cancer Gene Variant Database (3x, as uncertain). The variant was not identified in COGR, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, or the Mismatch Repair Genes Variant Database. The variant was identified in control databases in 75 of 270198 chromosomes at a frequency of 0.0003 in the following populations: African in 17 of 23654 chromosomes (freq. 0.0007), Latino in 13 of 34140 chromosomes (freq. 0.0004), European in 35 of 123578 chromosomes (freq. 0.0003), East Asian in 5 of 1860 chromosomes (freq. 0.0003), and other in 1 of 6346 chromosomes (freq. 0.0002), Ashkenazi Jewish in 1 of 10042 chromosomes (freq. 0.0001), South Asian in 3 of 30528 chromosomes (freq. 0.0001), increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). 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. A co-occurring pathogenic BRCA1 variant (c.709G>T, p.Glu237X) was identified in 1 individual with breast cancer in our laboratory, increasing the likelihood that c.4001+12_4001+15dupACTA variant does not have clinical significance 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.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000656542	SCV001744796	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000656542	SCV001808343	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000202155	SCV001921925	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000656542	SCV001972565	likely benign	not provided		no assertion criteria provided	clinical testing