ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.470G>C (p.Gly157Ala) (rs765489269)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000579889 SCV000685093 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-10 criteria provided, single submitter clinical testing
Counsyl RCV000662894 SCV000785812 uncertain significance Lynch syndrome I 2017-12-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000780448 SCV000917701 uncertain significance not specified 2017-09-15 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.470G>C (p.Gly157Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index), however these predictions have not been validated by functional studies. This variant was found in 1/246262 control chromosomes at a frequency of 0.0000041, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). The variant of interest has not, to our knowledge, been reported in affected individuals via publications. The variant has been reported in a reputable database and by one clinical diagnostic laboratory as uncertain significance. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV000197496 SCV000254424 uncertain significance Hereditary nonpolyposis colon cancer 2018-08-22 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 157 of the MSH2 protein (p.Gly157Ala). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and alanine. This variant is present in population databases (rs765489269, ExAC 0.001%). This variant has been reported in an individual in the Universal Mutation Database (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 216361). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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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