ClinVar Genomic variation as it relates to human health

The p.E13K variant (also known as c.37G>A), located in coding exon 1 of the MLH1 gene, results from a G to A substitution at nucleotide position 37. The glutamic acid at codon 13 is replaced by lysine, an amino acid with similar properties. This variant has been reported in 1/1120 pediatric cancer patients who underwent whole genome sequencing and/or whole exome sequencing; this patient was diagnosed with leukemia (Zhang J et al. N Engl J Med, 2015 Dec;373:2336-2346). This variant was also reported in a proband from Iceland diagnosed with colorectal cancer that demonstrated normal staining for the mismatch repair proteins on immunohistochemistry (Haraldsdottir S et al. Nat Commun, 2017 05;8:14755). 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 available evidence, the clinical significance of this alteration remains unclear.

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with mismatch repair-proficient colorectal cancer (Haraldsdottir et al., 2017); This variant is associated with the following publications: (PMID: 25741868, 22949387, 22753075, 28466842)

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 13 of the MLH1 protein (p.Glu13Lys). This variant is present in population databases (rs587779008, gnomAD 0.0009%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 28466842). ClinVar contains an entry for this variant (Variation ID: 192220). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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.

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.

This missense variant replaces glutamic acid with lysine at codon 13 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). To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer but was not significantly associated with cancer risk (PMID: 28466842). This variant has been identified in 1/251440 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.

This missense variant replaces glutamic acid with lysine at codon 13 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in individuals affected with colorectal cancer but was not significantly associated with cancer risk (PMID: 28466842). This variant has been identified in 1/251440 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.

The MLH1 p.Glu13Lys variant was identified in 1 of 16906 proband chromosomes (frequency: 0.00006) from Icelander population with Lynch Syndrome (Haraldsdottir 2017). The variant was also identified in dbSNP (ID: rs587779008) as “With Uncertain significance allele”, ClinVar (4x as uncertain significance by Ambry Genetics, Invitae, Counsyl, Pathway Genetics), Cosmic (Confirmed somatic carcinoma in bladder) and Insight Colon Cancer Gene Variant Database (1x as VUS). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 1 of 246240 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European Non-Finnish in 1 of 111694 chromosomes (freq: 0.000009), while the variant was not observed in the African, Other, Latino, Ashkenazi Jewish, East Asian, European Finnish, or South Asian populations. In addition the variant was identified in our laboratory in an individual with breast cancer, with a co-occurring pathogenic ATM variant (c.6916_6917del, p.Leu2307Cys*65), increasing the likelihood that the p.Glu13Lys variant does not have clinical significance The p.Glu13 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the (Glu) 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) 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.

DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.37G>A, in exon 1 that results in an amino acid change, p.Glu13Lys. This sequence change has not been previously described in individuals with MLH1 related disorders.This sequence change has been described in the gnomAD database in one individual which corresponds to a population frequency of 0.0004% (dbSNP rs587779008). The p.Glu13Lys change affects a highly conserved amino acid residue located in a domain of the MLH1 protein that is known to be functional. In-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL) provide contradictory results for the p.Glu13Lys substitution. Due to insufficient evidences and the lack of functional studies, the clinical significance of the p.Glu13Lys change remains unknown at this time.