ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1662-1G>A (rs267607970)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076224 SCV000107248 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Variant causes splicing aberration (full inactivation of variant allele)
Ambry Genetics RCV000491087 SCV000580617 pathogenic Hereditary cancer-predisposing syndrome 2019-04-01 criteria provided, single submitter clinical testing Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity;Rarity in general population databases (dbsnp, esp, 1000 genomes);Other data supporting pathogenic classification
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000076224 SCV000731656 pathogenic Lynch syndrome 2017-07-10 criteria provided, single submitter clinical testing The c.1662-1G>A variant in MSH2 has been reported as a germline variant in the h omozygous state in 1 individual with T-cell acute lymphoblastic leukemia and mul tiple cafe-au-lait spots (Whiteside 2002) and was absent in large population stu dies. This variant occurs in the invariant region (+/- 1,2) of the splice consen sus sequence and has shown to cause exon 11 skipping in blood derived patient RN A and results in an absent MSH2 protein (Whiteside 2002). Heterozygous loss of f unction of the MSH2 gene is an established disease mechanism in individuals with Lynch syndrome. Furthermore, the c.1662-1G>A variant has been classified as pat hogenic on Sept. 5th, 2013 by the ClinGen-approved InSiGHT expert panel (ClinVar SCV000107248.2). In summary, this variant meets criteria to be classified as pa thogenic for Lynch syndrome in an autosomal dominant manner based upon impact to the protein, functional studies and absence from controls.
Invitae RCV001239294 SCV001412155 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-11-12 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 10 of the MSH2 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be homozygous in an individual affected with clinical features of constitutional mismatch repair deficiency syndrome (PMID: 11809679). It has also been observed in an individual with colorectal cancer (PMID: 28944238). ClinVar contains an entry for this variant (Variation ID: 90727). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 11809679). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000001836 SCV000021992 pathogenic Turcot syndrome 2002-01-15 no assertion criteria provided literature only
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249923 SCV001423940 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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