ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2211-5T>G (rs368596736)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086513 SCV000254402 likely benign Hereditary nonpolyposis colorectal neoplasms 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000409905 SCV000488293 uncertain significance Lynch syndrome I 2016-03-08 criteria provided, single submitter clinical testing
GeneDx RCV000588531 SCV000565201 uncertain significance not provided 2018-08-07 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.2211-5T>G or IVS13-5T>G and consists of a T>G nucleotide substitution at the -5 position of intron 13 of the MSH2 gene. In silico analysis, which includes splice predictors and evolutionary conservation, supports a deleterious effect. However, in the absence of RNA or functional studies, the actual effect of this variant is unknown. MSH2 c.2211-5T>G has been observed in at least one individual with a personal history of Lynch syndrome-associated cancer and/or polyps (Yurgelun 2015). This variant was not observed at a significant allele frequency in large population cohorts (Lek 2016). Based on currently available evidence, it is unclear whether MSH2 c.2211-5T>G is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000568854 SCV000662243 uncertain significance Hereditary cancer-predisposing syndrome 2019-10-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000588531 SCV000696240 uncertain significance not provided 2017-01-16 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2211-5T>G variant involves the alteration of a conserved intronic nucleotide, which 4/5 splice prediction tools predict an alteration to splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 1/121160 control chromosomes at a frequency of 0.0000083, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). This variant has been reported in one individual undergoing Lynch Syndrome testing. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/VUS. Taken together, this variant is classified as a Variant of Uncertain Significance, until more information becomes available.
Color RCV000568854 SCV000903117 likely benign Hereditary cancer-predisposing syndrome 2016-04-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000409905 SCV001300496 uncertain significance Lynch syndrome I 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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