ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.778C>T (p.Leu260Phe) (rs63750642)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130511 SCV000185380 likely benign Hereditary cancer-predisposing syndrome 2017-10-09 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Other data supporting benign classification
GeneDx RCV000479043 SCV000569663 uncertain significance not provided 2017-08-23 criteria provided, single submitter clinical testing This variant is denoted MLH1 c.778C>T at the cDNA level, p.Leu260Phe (L260F) at the protein level, and results in the change of a Leucine to a Phenylalanine (CTC>TTC). This variant co-occurred with a pathogenic MSH2 variant in two relatives with early-onset colon cancer belonging to a German family meeting Amsterdam-1 criteria (Hardt 2011). Immunohistochemistry (IHC) on one of the colon tumors demonstrated expression of the MLH1 and PMS2 proteins (Hardt 2011). MSH2 Leu260Phe has also been identified in at least one other individual with a personal and family history suggestive of Lynch syndrome, and an ex vivo splicing assay showed that this variant does not affect splicing (Tournier 2008). However, to our knowledge, the functional impact of the amino acid substitution at the protein level has not been reported. The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as of uncertain significance (Thompson 2014). MLH1 Leu260Phe was not observed 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. MLH1 Leu260Phe occurs at a position that is conserved across species and is located in the N-terminal ATPase domain (Andersen 2012). 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 Leu260Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color Health, Inc RCV000130511 SCV000684864 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-03 criteria provided, single submitter clinical testing This missense variant replaces leucine with phenylalanine at codon 260 of the MLH1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study has shown that this variant causes a partial loss of MMR function in methylation tolerance-based functional assay (PMID: 30998989) and does not impact RNA splicing in minigene assay and in RT-PCR using cells from an individual who carries this variant (PMID: 18561205). This variant has been reported in two families affected with Lynch syndrome (PMID: 18561205, 21404117) and in an individual affected with breast cancer (PMID: 12173039). In one of the Lynch syndrome families who harbored this variant, two family members affected with colon cancer were determined to carry another pathogenic variant in the MSH2 gene, which could explain the observed phenotype (PMID: 21404117). This variant has been identified in 1/250762 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Invitae RCV000705556 SCV000834557 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-10-25 criteria provided, single submitter clinical testing This sequence change replaces leucine with phenylalanine at codon 260 of the MLH1 protein (p.Leu260Phe). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 30998989, 21404117). However, it at least one individual, pathogenic alleles were also identified in MSH2, which suggests that this c.778C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 90349) This variant has been reported to affect MLH1 protein function (PMID: 30998989). This variant disrupts the p.Leu260 amino acid residue in MLH1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 27629256, 24362816, 22290698). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000479043 SCV001153838 uncertain significance not provided 2018-07-01 criteria provided, single submitter clinical testing

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