ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.211G>C (p.Gly71Arg) (rs587782659)

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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 RCV000132075 SCV000187139 pathogenic Hereditary cancer-predisposing syndrome 2020-05-10 criteria provided, single submitter clinical testing The c.211G>C pathogenic mutation (also known as p.G71R), located in coding exon 1 of the MSH2 gene, results from a G to C substitution at nucleotide position 211. The glycine at codon 71 is replaced by arginine, an amino acid with dissimilar properties. However, this change occurs in the last base pair of coding exon 1, which makes it likely to have some effect on normal mRNA splicing. In one study, this variant was detected in two unrelated individuals diagnosed with early-onset colon cancer whose tumors showed loss of MSH2 and MSH6 protein expression on immunohistochemistry (IHC). Both families met Bethesda criteria and this variant was not detected in 188 controls. Further RNA studies indicated that this variant led to a partial deletion of exon 1 resulting in a premature truncation of the MSH2 protein (Vargas-Parra GM et al. Int. J. Cancer. 2017 10;141:1365-1380). This variant has also been identified in several individuals whose Lynch syndrome-associated tumors demonstrated high microsatellite instability and/or loss of MSH2 and MSH6 protein expression on IHC (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice donor site; however, direct evidence is unavailable. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000535324 SCV000625353 likely pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-08-19 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 71 of the MSH2 protein (p.Gly71Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. It also falls at the last nucleotide of exon 1 of the MSH2 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with Lynch syndrome (PMID: 28577310) and has been observed to segregate with Lynch syndrome-associated tumors in a single family (Invitae). ClinVar contains an entry for this variant (Variation ID: 142708). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; Align-GVGD: Class C0). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of nucleotide changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985801 SCV001134350 likely pathogenic not provided 2019-05-15 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/221594 chr). Found in at least one symptomatic patient in literature. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000503476 SCV001337820 likely pathogenic Lynch syndrome 2020-01-14 criteria provided, single submitter clinical testing Variant summary: MSH2 c.211G>C (p.Gly71Arg) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) of the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function and weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing and results in aberrant transcript which is predicted to generate a truncated protein (p.Tyr66Serfs*10) (Vargas-Parra_2017). The variant was absent in 218268 control chromosomes (gnomAD). c.211G>C has been reported in the literature in individuals affected with Lynch Syndrome, including one family suggesting co-segregation of the variant and the disease (Vargas-Parra_2017). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Color Health, Inc RCV000132075 SCV001342611 likely pathogenic Hereditary cancer-predisposing syndrome 2019-04-08 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353465 SCV000592455 likely pathogenic Carcinoma of colon no assertion criteria provided clinical testing The p.Gly71Arg variant has not been reported in the literature nor previously identified by our laboratory. The variant occurs in the last base of exon 1. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In-silico or computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predicts a greater than 10% difference in splicing in 4 out of 5 different programs. This residue is conserved in mammals but not in lower organisms, and computational analyses (SIFT, AlignGVGD) do not suggest a high likelihood of impact to the protein. However, the information from these software analyses is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time, although we would lean towards a more pathogenic role for this variant. This variant is classified as Predicted Pathogenic.

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