ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.403C>T (p.Leu135Phe) (rs193096019)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115530 SCV000149439 uncertain significance not provided 2017-04-11 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.403C>T at the cDNA level, p.Leu135Phe (L135F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant has been observed in at least one individual referred for clinical testing for hereditary cancer (Mu 2016). MSH2 Leu135Phe was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Leucine and Phenylalanine share similar properties, this is considered a conservative amino acid substitution. MSH2 Leu135Phe occurs at a position that is conserved across species and is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH2 Leu135Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000199902 SCV000254422 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 135 of the MSH2 protein (p.Leu135Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is present in population databases (rs193096019, ExAC 0.001%). This variant has been reported in an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 127646). 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: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, this variant is a rare missense change with uncertain impact on protein function. It has been reported in both the population and affected individuals, but the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000217044 SCV000275551 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Counsyl RCV000411543 SCV000489067 uncertain significance Lynch syndrome I 2016-08-12 criteria provided, single submitter clinical testing
Color RCV000217044 SCV000685090 uncertain significance Hereditary cancer-predisposing syndrome 2020-02-12 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001175574 SCV001339207 uncertain significance not specified 2020-03-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.403C>T (p.Leu135Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251312 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.403C>T has been reported in the literature in an individual affected with breast cancer (Tung_2015) and in a study reporting results from hereditary-cancer NGS panels (Mu_2016). 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. Five 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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