ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2354A>G (p.His785Arg) (rs200252727)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213407 SCV000274282 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
CSER_CC_NCGL; University of Washington Medical Center RCV000735967 SCV000864156 uncertain significance Colorectal cancer 2017-07-01 criteria provided, single submitter research Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 77 year old female diagnosed with colon cancer at age 74. Family history of colorectal cancer and/or polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review.
Color RCV000213407 SCV000685036 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-29 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589584 SCV000696246 uncertain significance not provided 2017-05-23 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.2354A>G (p.His785Arg) variant involves the alteration of a conserved nucleotide, is located in DNA mismatch repair protein MutS, C-terminal domain/P-loop containing nucleoside triphosphate hydrolase domain (InterPro) and is predicted to be damaging by 4/4 in silico tools (SNPsandGO not captured due to low reliability index). This variant is absent in 121394 control chromosomes from ExAC; however it is present at an allele frequency of 0.0000072 (2/277196 chromosomes) in gnomAD database which is lower that the maximal expected allele frequency of a pathogenic MSH2 variant (0.00056). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Another missense change at the same residue p.H785P has been reported in a familial CRC patient (PMID: 25559809) and is classified as VUS in ClinVar by multiple submitters. 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.
Invitae RCV000168313 SCV000218997 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-19 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 785 of the MSH2 protein (p.His785Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. 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: 188316). 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 disruptive, 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.

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