ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.4_21dup (p.Ala2_Glu7dup) (rs281864943)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221366 SCV000273168 uncertain significance Hereditary cancer-predisposing syndrome 2019-07-01 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Insufficient evidence
GeneDx RCV000586230 SCV000279602 uncertain significance not provided 2015-12-22 criteria provided, single submitter clinical testing This in-frame duplication of 18 nucleotides in MSH2 is denoted c.4_21dup18 at the cDNA level and p.Ala2_Glu7dup (A2_E7dup) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is cATG{dup18}ACGC. The duplicated amino acids are all conserved through species except for the last amino acid, a Glutamic Acid, which is not conserved. This duplication is located in the mismatch binding domain (Lutzen 2008). This variant was reported in an individual with a MSI-High colorectal cancer: however, this tumor was shown to have normal immunohistochemical staining for the Lynch related proteins (Krüger 2003). Since in-frame duplications may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider MSH2 Ala2_Glu7dup to be a variant of uncertain significance.
Color RCV000221366 SCV000685088 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-27 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000586230 SCV000696267 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.4_21dupGCGGTGCAGCCGAAGGAG (p.Ala2_Glu7dup) variant leads to a duplication of six amino acids (AVQPKE) in exon 1. Mutation taster predicts a benign outcome for this variant. This variant was found in 1/37562 control chromosomes including ExAC at a frequency of 0.0000266, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). This variant has been reported in two patients (one with colon cancer not fulfilling Bethesda criteria and another with Lynch Syndrome patient fulfilling modified Bethesda criteria) without strong evidence for or against pathogenicity (Kruger_2003, Mangold_2005). Tumor from one of the patients showed MSH-I but normal expression of MMR proteins (Kruger_2003). Multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Therefore, until additional information becomes available (ie, clinical and functional studies), the variant of interest has been classified as a "Variant of Uncertain Significance (VUS)."
Invitae RCV000813731 SCV000954102 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-03-19 criteria provided, single submitter clinical testing This variant, c.4_21dup, results in the insertion of 6 amino acids to the MSH2 protein (p.Ala2_Glu7dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has been observed in an individual affected with Lynch syndrome (PMID: 15849733). ClinVar contains an entry for this variant (Variation ID: 91114). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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