ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1657A>T (p.Asn553Tyr) (rs772772789)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000477039 SCV000548250 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with tyrosine at codon 553 of the MSH2 protein (p.Asn553Tyr). The asparagine residue is highly conserved and there is a large physicochemical difference between asparagine and tyrosine. This variant is present in population databases (rs772772789, ExAC 0.001%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 408518). 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.
Color RCV000774572 SCV000908312 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000774572 SCV001173054 uncertain significance Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing The p.N553Y variant (also known as c.1657A>T), located in coding exon 10 of the MSH2 gene, results from an A to T substitution at nucleotide position 1657. The asparagine at codon 553 is replaced by tyrosine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao EC et al. Hum. Mutat. 2008 Jun;29:852-60). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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