ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.2048T>C (p.Phe683Ser) (rs587778972)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000075497 SCV000106493 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Posterior probability=0.990 therefore Class 4 because not greater than 0.99
GeneDx RCV000589365 SCV000279952 uncertain significance not provided 2017-10-17 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.2048T>C at the cDNA level, p.Phe683Ser (F683S) at the protein level, and results in the change of a Phenylalanine to a Serine (TTC>TCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Phe683Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Phenylalanine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MLH1 Phe683Ser occurs at a position that is conserved across species and is located within the region of interaction with PMS2/MLH3/PMS1 (Pang 1997, Raevaara 2005, Hardt 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 MLH1 Phe683Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000790627 SCV000696140 uncertain significance not specified 2019-04-24 criteria provided, single submitter clinical testing Variant summary: MLH1 c.2048T>C (p.Phe683Ser) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251222 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. In the Leiden Open Variation database (LOVD), the variant has been reported in two individuals with colorectal cancer. To our knowledge, no occurrence of c.2048T>C in individuals affected with Lynch Syndrome and no experimental evidence demonstrating its impact on protein function have been reported in the published peer-reviewed literature. Two other submitters including one expert panel have provided clinical significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. While the expert panel classifies the variant as likely pathogenic based on a posterior probability model another submitter reports a classification of uncertain significance. Therefore this variant is classified as uncertain significance until additional evidence becomes available.
Ambry Genetics RCV001014231 SCV001174916 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-15 criteria provided, single submitter clinical testing The p.F683S variant (also known as c.2048T>C), located in coding exon 18 of the MLH1 gene, results from a T to C substitution at nucleotide position 2048. The phenylalanine at codon 683 is replaced by serine, an amino acid with highly dissimilar properties. This alteration was identified in an individual whose family history met Amsterdam I criteria for Lynch syndrome and colorectal tumor displayed high microsatellite instability (MSI-H) with loss of both MLH1/PMS2 protein expression on immunohistochemistry (IHC) (Ambry internal data). Furthermore, this alteration segregated with disease in 4 affected relatives in this family (Ambry internal data). Based on an internal structural assessment, this alteration significantly decreases structural stability of the C-terminal domain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature. 2016 08;536:285-91). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. In addition, this alteration is predicted to be borderline deleterious by MAPP-MMR in silico analyses (Chao E et al. Hum Mutat. 2008 Jun;29(6):852-60). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV001209526 SCV001380964 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-06-28 criteria provided, single submitter clinical testing This sequence change replaces phenylalanine with serine at codon 683 of the MLH1 protein (p.Phe683Ser). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with Lynch syndrome associated cancers in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 90012). 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001355274 SCV001550108 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The variant p.Phe683Ser was not identified in the literature. This variant is listed in the dbSNP database (ID#: rs587778972), but no frequency information was provided, thus the prevalence of this variant in the general population could not be determined. This variant was also identified in Clinvitae database (Uncertain Significance), InSiGHT Colon Cancer Gene Variant Database (LOVD), ClinVar database (as uncertain significance, by Insight and GeneDx). This variant was not identified in the 1000 Genomes Project, the NHLBI Exome Sequencing Project, the Exome Aggregation Consortium, the genome Aggregation Database (beta), GeneInsight COGR, COSMIC, MutDB, UMD, the Zhejiang Colon Cancer Database (LOVD), the “Mismatch Repair Genes Variant Database” or the “MMR Gene Unclassified Variants Database”. The p.Phe683 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the p.Phe683Ser variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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