ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.123C>G (p.Asp41Glu) (rs761960690)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166062 SCV000216824 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000228645 SCV000284100 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-20 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 41 of the MSH2 protein (p.Asp41Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 186463). 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. 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 RCV000589227 SCV000565182 uncertain significance not provided 2017-10-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.123C>G at the cDNA level, p.Asp41Glu (D41E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAC>GAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Asp41Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Aspartic Acid and Glutamic Acid share similar properties, this is considered a conservative amino acid substitution. MSH2 Asp41Glu occurs at a position that is conserved across species and is located within the 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 Asp41Glu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589227 SCV000696203 uncertain significance not provided 2016-12-22 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.123C>G (p.Asp41Glu) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 71272 control chromosomes. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
Counsyl RCV000662660 SCV000785349 uncertain significance Lynch syndrome I 2017-07-21 criteria provided, single submitter clinical testing
Color RCV000166062 SCV000903263 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-12 criteria provided, single submitter clinical testing

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