Submissions for variant NM_000249.4(MLH1):c.2048T>C (p.Phe683Ser)

dbSNP: rs587778972

Total submissions: 7

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	RCV005237504	SCV000696140	likely pathogenic	Hereditary nonpolyposis colon cancer	2024-12-30	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 (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. c.2048T>C has been observed in individuals with a personal and family history of Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer at our laboratory (internal testing). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 90012). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Ambry Genetics	RCV001014231	SCV001174916	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-13	criteria provided, single submitter	clinical testing	The p.F683S pathogenic mutation (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 is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001209526	SCV001380964	likely pathogenic	Hereditary nonpolyposis colorectal neoplasms	2023-08-27	criteria provided, single submitter	clinical testing	This sequence change replaces phenylalanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 683 of the MLH1 protein (p.Phe683Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Lynch syndrome (Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 90012). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MLH1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Myriad Genetics, Inc.	RCV003451098	SCV004188210	likely pathogenic	Colorectal cancer, hereditary nonpolyposis, type 2	2023-07-25	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [Myriad internal data]. This variant is expected to disrupt protein structure [Myriad internal data].
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.