ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2260A>G (p.Thr754Ala) (rs757268664)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000196465 SCV000254403 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 754 of the MSH2 protein (p.Thr754Ala). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs757268664, ExAC 0.02%). This variant has been observed in an individual with clinical features of Lynch syndrome (PMID: 29212164). ClinVar contains an entry for this variant (Variation ID: 216352). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Ambry Genetics RCV000560982 SCV000662296 uncertain significance Hereditary cancer-predisposing syndrome 2016-07-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000560982 SCV000685028 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-25 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589091 SCV000696243 uncertain significance not provided 2016-06-14 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2260A>G (p.Thr754Ala) variant causes a missense change involving a conserved nucleotide with 4/4 in silico tools (SNPs&GO not captured due to low reliability index) predicting a damaging outcome for this variant, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 2/121344 (1/60672), which does not exceed the estimated maximal expected allele frequency for a pathogenic MSH2 variant of 1/1759 (0.0005683). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, however, a clinical laboratory does cite the variant as "uncertain significance." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.

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