ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2164G>A (p.Val722Ile) (rs587781996)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130409 SCV000185271 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000168465 SCV000219164 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-27 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 722 of the MSH2 protein (p.Val722Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is present in population databases (rs587781996, ExAC 0.02%). This variant has been observed in individuals with colorectal cancer (PMID: 19697156, 27601186, 10612827). However, in one of these individuals a pathogenic allele was also identified in MSH2, which suggests that this c.2164G>A variant was not the primary cause of disease (PMID: 10612827). ClinVar contains an entry for this variant (Variation ID: 141769). Experimental studies have shown that this missense change behaves as wild-type in a mismatch repair (MMR) activity and protein stability assay (PMID: 19697156). 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 RCV000487305 SCV000565993 likely benign not specified 2018-03-09 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Color RCV000130409 SCV000910890 likely benign Hereditary cancer-predisposing syndrome 2015-03-12 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000509191 SCV001250443 uncertain significance not provided 2019-10-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000487305 SCV001432024 uncertain significance not specified 2020-08-25 criteria provided, single submitter clinical testing Variant summary: MSH2 c.2164G>A (p.Val722Ile) results in a conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251484 control chromosomes, predominantly at a frequency of 9.7e-05 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (5.2e-05 vs 0.00057), allowing no conclusion about variant significance. c.2164G>A has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer (e.g. Christensen_2009, Haraldsdottir_2017, Lagerstedt-Robinson_2016). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.1929delG, p.Arg645Glufs), providing supporting evidence for a benign role (Dominguez-Valentin_2018). In in vitro functional studies, the variant was found to have normal mismatch repair (MMR) activity similar to wild type (Christensen_2009). Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=3) or likely benign (n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
GenomeConnect, ClinGen RCV000509191 SCV000607173 not provided not provided no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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