Submissions for variant NM_000251.3(MSH2):c.1387-14_1387-11del

dbSNP: rs370436680

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000679288	SCV000565192	likely benign	not provided	2022-06-06	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Color Diagnostics, LLC DBA Color Health	RCV000579543	SCV000684935	benign	Hereditary cancer-predisposing syndrome	2015-11-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679288	SCV000805996	likely benign	not provided	2017-11-10	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000478880	SCV001360861	benign	not specified	2019-01-24	criteria provided, single submitter	clinical testing	Variant summary: The variant, MSH2 c.1387-14_1387-11delTGTT alters non-conserved nucleotides located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 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 0.00064 in 276896 control chromosomes, predominantly at a frequency of 0.0056 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 9.85 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.1387-14_1387-11delTGTT in individuals affected with Lynch Syndrome or Hereditary nonpolyposis colorectal cancer (HNPCC) and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002063693	SCV002392242	benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-08	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000679288	SCV002506143	likely benign	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000579543	SCV002528841	benign	Hereditary cancer-predisposing syndrome	2021-10-25	criteria provided, single submitter	curation
Ambry Genetics	RCV000579543	SCV002702621	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-11	criteria provided, single submitter	clinical testing	The c.1387-14_1387-11delTGTT intronic variant results from a deletion of 4 nucleotides beginning 14 nucleotides upstream from coding exon 9 in the MSH2 gene. These nucleotide positions are poorly conserved on available sequence alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native acceptor splice site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV004806349	SCV005429104	benign	Lynch syndrome	2024-09-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000478880	SCV005873516	benign	not specified	2025-03-04	criteria provided, single submitter	clinical testing	Classification criteria: BA1
Myriad Genetics, Inc.	RCV005248054	SCV005897123	benign	Lynch syndrome 1	2024-12-09	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: 27363726].