ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1108G>A (p.Ala370Thr) (rs1064794109)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000480197 SCV000567860 uncertain significance not provided 2016-04-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1108G>A at the cDNA level, p.Ala370Thr (A370T) at the protein level, and results in the change of an Alanine to a Threonine (GCA>ACA). This variant has been observed in at least one family with Lynch syndrome (Tang 2009). MSH2 Ala370Thr was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Alanine and Threonine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Ala370Thr occurs at a position that is not conserved and is located within the lever domain (Lutzen 2008). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available information, it is unclear whether MSH2 Ala370Thr is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000529519 SCV000625228 uncertain significance Hereditary nonpolyposis colon cancer 2019-10-19 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 370 of the MSH2 protein (p.Ala370Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in a family affected with Lynch syndrome (PMID: 19419416). ClinVar contains an entry for this variant (Variation ID: 419793). Experimental studies have shown that this missense does not affect protein function (PMID: 29731845). 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 RCV001017344 SCV001178416 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-13 criteria provided, single submitter clinical testing Insufficient evidence
Color RCV001017344 SCV001353478 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-12 criteria provided, single submitter clinical testing

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