ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.146A>T (p.Asp49Val) (rs63750335)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160615 SCV000211212 uncertain significance not provided 2017-03-15 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.146A>T at the cDNA level, p.Asp49Val (D49V) at the protein level, and results in the change of an Aspartic Acid to a Valine (GAC>GTC). This variant was observed in at least one individual with colorectal cancer (Papp 2007). In addition, a yeast-based mutator assay predicted this variant to have a loss of normal function (Martinez 2010). However, The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as having uncertain significance (Thompson 2014). MSH2 Asp49Val was not observed at a significant frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Aspartic Acid and Valine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Asp49Val occurs at a position that is conserved across species and is located in mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Asp49Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000221403 SCV000277722 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Invitae RCV000684812 SCV000548154 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-11 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with valine at codon 49 of the MSH2 protein (p.Asp49Val). The aspartic acid residue is highly conserved and there is a large physicochemical difference between aspartic acid and valine. This variant is present in population databases (rs63750335, ExAC 0.002%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 17569143). ClinVar contains an entry for this variant (Variation ID: 90675). This variant has been reported to affect MSH2 protein function (PMID: 20176959). 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 RCV000221403 SCV000684939 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-12 criteria provided, single submitter clinical testing
Counsyl RCV000662586 SCV000785212 uncertain significance Lynch syndrome I 2017-06-02 criteria provided, single submitter clinical testing

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