ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1927G>A (p.Glu643Lys) (rs374840361)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000589876 SCV000211192 uncertain significance not provided 2018-06-29 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.1927G>A at the cDNA level, p.Glu643Lys (E643K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant has been observed in at least one woman with ovarian cancer (Pal 2012). MSH2 Glu643Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase Domain (L?tzen 2008). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Glu643Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000160596 SCV000216735 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-21 criteria provided, single submitter clinical testing The p.E643K variant (also known as c.1927G>A), located in coding exon 12 of the MSH2 gene, results from a G to A substitution at nucleotide position 1927. The glutamic acid at codon 643 is replaced by lysine, an amino acid with similar properties. This alteration was detected in one individual in a population-based study of 1893 women with ovarian cancer (<span style="background-color:initial">Pal T et al. Br. J. Cancer. 2012 Nov;107:1783-90) as well as in an individual with apparently sporadic pancreatic cancer (Shindo K et al. J. Clin. Oncol. 2017 Oct;35:3382-3390).<span style="background-color:initial"> This variant has also been seen in an exome cohort, but cancer history was not provided (Amendola LM et al. Genome Res. 2015 Mar;25:305-15). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000204646 SCV000261595 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-30 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 643 of the MSH2 protein (p.Glu643Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549) and with pancreatic ductal adenocarcinoma (PMID: 28767289). It has also been observed on the opposite chromosome (in trans) from a pathogenic whole gene deletion of MSH2 in an individual affected with an unspecified gynecological cancer (Invitae), suggesting that this c.1927G>A change was not the primary cause of disease in that individual. ClinVar contains an entry for this variant (Variation ID: 161299). 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.
Color RCV000160596 SCV000690031 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589876 SCV000696229 uncertain significance not provided 2016-09-30 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.1927G>A (p.Glu643Lys) variant involves the alteration of a conserved nucleotide. This missense variant is located at a highly conserved amino acid across species and is located in the DNA mismatch repair protein MutS, core and P-loop containing nucleoside triphosphate hydrolase domains (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/130004 control chromosomes at a frequency of 0.0000077, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). There is one published report of an epithelial ovarian cancer pt carrying the variant in heterozygous state; however, no co-segregation or co-occurrence data were provided, thus it cannot be concluded that the variant was causal. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as variant of uncertain significance. Taken together, this variant is classified as VUS until additional information is available.
Fulgent Genetics,Fulgent Genetics RCV000765671 SCV000897013 uncertain significance Lynch syndrome I; Turcot syndrome; Muir-Torré syndrome 2018-10-31 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148637 SCV000190352 uncertain significance Ovarian cancer 2014-06-01 no assertion criteria provided research

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