ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.328A>C (p.Lys110Gln) (rs587779970)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115526 SCV000149435 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.328A>C at the cDNA level, p.Lys110Gln (K110Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant was observed in an individual with both colon and rectal cancers (de Rosa 2016). MSH2 Lys110Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the mismatch binding domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH2 Lys110Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000475276 SCV000548227 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-15 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamine at codon 110 of the MSH2 protein (p.Lys110Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with colorectal cancer (PMID: 27432916). ClinVar contains an entry for this variant (Variation ID: 127642). 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.
Ambry Genetics RCV000567258 SCV000662237 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing The p.K110Q variant (also known as c.328A>C), located in coding exon 2 of the MSH2 gene, results from an A to C substitution at nucleotide position 328. The lysine at codon 110 is replaced by glutamine, an amino acid with similar properties. This alteration was detected in an individual with rectal cancer diagnosed at age 36 and an additional diagnosis of colon cancer whose personal and family history met Bethesda but not Amsterdam I or II criteria (de Rosa N et al. J. Clin. Oncol. 2016 Sep;34:3039-46). This amino acid position is highly conserved in available vertebrate species. In addition, 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.
Color RCV000567258 SCV000685079 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001269195 SCV001448492 uncertain significance not specified 2020-11-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.328A>C (p.Lys110Gln) results in a conservative amino acid change located in the DNA mismatch repair protein MutS-like, N-terminal domain (IPR007695) 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 4e-06 in 251294 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.328A>C has been reported in the literature in an individual affected with colon and rectal cancer (deRosa_2016). This report however, does not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

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