ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1661G>A (p.Ser554Asn) (rs63750597)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570315 SCV000669713 pathogenic Hereditary cancer-predisposing syndrome 2019-05-01 criteria provided, single submitter clinical testing Last nucleotide of exon;Functionally-validated splicing mutation;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Invitae RCV000802215 SCV000942036 likely pathogenic Hereditary nonpolyposis colon cancer 2019-01-05 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 554 of the MSH2 protein (p.Ser554Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant also falls at the last nucleotide of exon 10 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is present in population databases (rs63750597, ExAC 0.001%). This variant has been observed to segregate with Lynch syndrome-associated cancers in a large family (PMID: 21778331, 23523604). ClinVar contains an entry for this variant (Variation ID: 483664). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 19250818). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

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