ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.220A>C (p.Asn74His) (rs150548839)

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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 RCV000571485 SCV000662249 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Color RCV000571485 SCV000685023 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-30 criteria provided, single submitter clinical testing
Counsyl RCV000409685 SCV000489575 uncertain significance Lynch syndrome I 2016-10-26 criteria provided, single submitter clinical testing
GeneDx RCV000587188 SCV000211178 uncertain significance not provided 2017-06-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.220A>C at the cDNA level, p.Asn74His (N74H) at the protein level, and results in the change of an Asparagine to a Histidine (AAT>CAT). This variant was identified in 1/331 healthy European individuals undergoing whole genome sequencing (Bodian 2014). Of note, the participants in this study were younger than 50 years old thus the unaffected status of this individual may not be significant. MSH2 Asn74His was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Asparagine and Histidine differ in some properties, this is considered a semi-conservative amino acid substitution. MSH2 Asn74His occurs at a position that is not conserved and is located within the mismatch binding domain (Lutzen 2008, Kansikas 2011). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether MSH2 Asn74His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
ITMI RCV000121566 SCV000085760 not provided not specified 2013-09-19 no assertion provided reference population
Integrated Genetics/Laboratory Corporation of America RCV000587188 SCV000696239 uncertain significance not provided 2016-09-05 criteria provided, single submitter clinical testing Variant summary: The MSH2 c.220A>C (p.Asn74His) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 3/122484 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.00003 (2/66628). This frequency is lower than the estimated maximal expected allele frequency of a pathogenic MSH2 variant (0.0005683). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories, nor evaluated for functional impact by in vivo/vitro studies. 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 RCV000230947 SCV000284141 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces asparagine with histidine at codon 74 of the MSH2 protein (p.Asn74His). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and histidine. This variant is present in population databases (rs150548839, ExAC 0.003%). This variant has not been reported in the literature in individuals with MSH2-related disease. ClinVar contains an entry for this variant (Variation ID: 134846). 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: "Benign"; 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.

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