ClinVar Miner

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

dbSNP: rs370436680
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Total submissions: 8
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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.
Invitae RCV002063693 SCV002392242 benign Hereditary nonpolyposis colorectal neoplasms 2024-01-31 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.

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