ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.14C>A (p.Pro5Gln) (rs56170584)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165088 SCV000215793 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence;Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Invitae RCV000524345 SCV000218965 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-23 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 5 of the MSH2 protein (p.Pro5Gln). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is present in population databases (rs56170584, ExAC 0.09%). This variant has been reported in a family with Lynch syndrome (PMID: 14514376), individuals with clinical features of Lynch syndrome (PMID: 26845104, 29050249, 31307542), as well as in individuals with breast cancer (PMID: 28580595). ClinVar contains an entry for this variant (Variation ID: 90682). 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: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000076178 SCV000266193 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Counsyl RCV000412350 SCV000487994 uncertain significance Lynch syndrome I 2015-12-10 criteria provided, single submitter clinical testing
Color RCV000165088 SCV000537564 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000486935 SCV000568618 uncertain significance not provided 2018-04-11 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.14C>A at the cDNA level, p.Pro5Gln (P5Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). This variant was observed in at least one individual meeting Amsterdam criteria for Lynch syndrome and other individuals with breast or stomach cancer (Sun 2004, Shirts 2016, Kim 2017, Xie 2017), but has also been observed in at least three healthy Japanese individuals undergoing whole genome sequencing (Yamaguchi-Kabata 2018). Functional study of this variant demonstrated significant defects in RNA and protein expression, as well as cell viability and response to DNA-damaging agents (Arora 2017). MSH2 Pro5Gln was observed at an allele frequency of 0.045% (7/15,668) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located within the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Pro5Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781557 SCV000919696 uncertain significance not specified 2018-03-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.14C>A (p.Pro5Gln) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7e-05 in 42616 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MSH2 causing Lynch Syndrome (7e-05 vs 0.00057), allowing no conclusion about variant significance. c.14C>A has been reported in the literature in individuals affected with Lynch Syndrome or stomach cancer. These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Mendelics RCV000412350 SCV001135687 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030703 SCV001193625 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research

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