ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1979A>G (p.Asp660Gly) (rs1085308057)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000490598 SCV000579291 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability 0.95-0.99
Ambry Genetics RCV000491547 SCV000580406 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-19 criteria provided, single submitter clinical testing The p.D660G variant (also known as c.1979A>G), located in coding exon 12 of the MSH2 gene, results from an A to G substitution at nucleotide position 1979. The aspartic acid at codon 660 is replaced by glycine. This variant is in the ABC-ATPase domain of the protein in close proximity to a highly conserved Walker A/P-Loop motif (Warren et al. Molecular Cell 26, 579–592, May 25, 2007). This alteration was detected in two individuals meeting Bethesda criteria, and tumor studies of one patient’s tumor showed loss of MSH2 and MSH6 proteins with immunohistochemistry and was microsatellite unstable (Taylor CF et al. Hum. Mutat. 2003 Dec;22:428-33; Sjursen et al. J. Med. Genet. 2010 Sep;47:579-85; personal communication with Dr. Sjursen). In addition, Sjursen et al. showed that this alteration resulted in abnormal RNA splicing in patient lymphocytes (Sjursen et al. J. Med. Genet. 2010 Sep;47:579-85). This amino acid position is not well conserved, however, glycine is the reference amino acid in several species. Using three splice site prediction tools, Human Splicing Finder, Exonic Splicing Enhancer (ESE), and Fruitfly, this alteration was predicted to create a stronger alternate splice donor site that may lead to abnormal splicing. Based on the majority of evidence to date, this variant is likely to be pathogenic.
Color RCV000491547 SCV000910479 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-23 criteria provided, single submitter clinical testing
Invitae RCV001039917 SCV001203467 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-05-14 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 660 of the MSH2 protein (p.Asp660Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with clinical features of Lynch syndrome (PMID: 14635101, 20587412). ClinVar contains an entry for this variant (Variation ID: 427603). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glycine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.

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