ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.232G>A (p.Val78Ile) (rs772779997)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000229561 SCV000284149 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-14 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 78 of the MSH2 protein (p.Val78Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs772779997, ExAC 0.02%). This variant has been observed in an individual affected with familial non-medullary thyroid cancer (PMID: 26530882). ClinVar contains an entry for this variant (Variation ID: 237389). 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.
GeneDx RCV000235910 SCV000292781 uncertain significance not provided 2017-04-02 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.232G>A at the cDNA level, p.Val78Ile (V78I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). This variant has been observed in one individual with non-medullary thyroid carcinoma (Yu 2015). MSH2 Val78Ile was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. MSH2 Val78Ile occurs at a position that is conserved across species and is located within the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Val78Ile is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491448 SCV000580552 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000491448 SCV000685033 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-03 criteria provided, single submitter clinical testing

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