ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.1514G>A (p.Ser505Asn) (rs771044689)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164523 SCV000215176 uncertain significance Hereditary cancer-predisposing syndrome 2017-05-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000205482 SCV000261528 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces serine with asparagine at codon 505 of the MLH1 protein (p.Ser505Asn). The serine residue is highly conserved and there is a small physicochemical difference between serine and asparagine. This variant is present in population databases (rs771044689, ExAC 0.004%). This variant has been reported in an individual with suspected Lynch syndrome (PMID: 23523604, 19250818). This variant is also known as c.1574G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 185154). 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 RCV000164523 SCV000292220 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
GeneDx RCV000481882 SCV000568568 uncertain significance not provided 2018-01-26 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.1514G>A at the cDNA level, p.Ser505Asn (S505N) at the protein level, and results in the change of a Serine to an Asparagine (AGT>AAT). This variant was observed in an individual suspected of having hereditary non-polyposis colorectal cancer (HNPCC) whose colorectal tumor was microsatellite stable (MSS) (Perez-Cabornero 2013). MLH1 Ser505Asn was observed at an allele frequency of 0.04% (4/10150) in individuals of Ashkenazi Jewish ancestry in large population cohorts (Lek 2016). MLH1 Ser505Asn is located within the region of interaction with PMS2, MLH3, PMS1, and EXO1 (Raevaara 2005, Kansikas 2010, Andersen 2012). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Ser505Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000663072 SCV000786144 uncertain significance Lynch syndrome II 2018-03-07 criteria provided, single submitter clinical testing
Mendelics RCV000708926 SCV000838020 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000481882 SCV001153845 uncertain significance not provided 2018-10-01 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.