Submissions for variant NM_000179.3(MSH6):c.4001+2TAAC[4]

dbSNP: rs267608132

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000160734	SCV000186783	likely benign	Hereditary cancer-predisposing syndrome	2013-03-21	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	RCV000204092	SCV000211370	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Counsyl	RCV000409636	SCV000489203	likely benign	Lynch syndrome 5	2016-09-07	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160734	SCV000685476	likely benign	Hereditary cancer-predisposing syndrome	2014-12-29	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780481	SCV000917766	benign	not specified	2018-06-07	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.4001+12_4001+15dupACTA alters a nucleotide located in the intronic region that is not widely known to affect splicing. 5/5 computational 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 0.00028 in 270198 control chromosomes. The observed variant frequency is approximately 2 fold above 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. To our knowledge, no occurrence of c.4001+12_4001+15dupACTA in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Multiple clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Mendelics	RCV000409636	SCV001135858	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001439800	SCV001642694	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000204092	SCV002496485	likely benign	not provided	2022-02-01	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000780481	SCV002552372	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505194	SCV002812470	likely benign	Endometrial carcinoma; Lynch syndrome 5; Mismatch repair cancer syndrome 3	2021-10-26	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000160734	SCV002819234	benign	Hereditary cancer-predisposing syndrome	2022-11-22	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492658	SCV004239323	likely benign	Breast and/or ovarian cancer	2023-05-19	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357088	SCV001552434	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: 0.00066) from individuals or families with CRC and was identified as 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), Insight Colon Cancer Gene Variant Database (3x, as Class 3), Insight Hereditary Tumors Database (3x), databases. The variant was not identified in GeneInsight-COGR, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, databases. The variant was identified in control databases in 75 of 270198 chromosomes at a frequency of 0.00028 in the following populations: African in 17 of 23654 chromosomes (freq. 0.0007), Latino in 13 of 34140 chromosomes (freq. 0.00038), European in 35 of 123578 chromosomes (freq. 0.00028), East Asian in 5 of 1860 chromosomes (freq. 0.00026), and other in 1 of 6346 chromosomes (freq. 0.00015), 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) is 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	RCV000204092	SCV001742143	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000204092	SCV001809143	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000780481	SCV001968316	benign	not specified		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004544472	SCV004778726	likely benign	MSH6-related disorder	2021-12-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).