ClinVar Genomic variation as it relates to human health

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 331 of the MLH1 protein (p.Glu331Lys). This variant is present in population databases (rs550914672, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of MLH1-related conditions and/or personal history of breast and/or ovarian cancer (PMID: 21520333, 26580448, 32068069). ClinVar contains an entry for this variant (Variation ID: 230317). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MLH1 protein function. 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.

The p.E331K variant (also known as c.991G>A), located in coding exon 11 of the MLH1 gene, results from a G to A substitution at nucleotide position 991. The glutamic acid at codon 331 is replaced by lysine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with breast and/or gynecologic cancer (PMID: 32068069); This variant is associated with the following publications: (PMID: 28481359, 22753075, 25892863, 32068069)

To our knowledge, this sequence variant has not been previously reported in the literature. This variant has an overall allele frequency of 0.00002 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3

DNA sequence analysis of the MLH1 gene demonstrated a sequence change, c.991G>A, in exon 11 that results in an amino acid change, p.Glu331Lys. This sequence change does not appear to have been previously described in individuals with MLH1-related disorders and has been described in the gnomAD database in six individuals with an overall population frequency of 0.0021% (dbSNP rs550914672). The p.Glu331Lys change affects a highly conserved amino acid residue located in a domain of the MLH1 protein that is known to be functional. The p.Glu331Lys substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Glu331Lys change remains unknown at this time.

Variant summary: MLH1 c.991G>A (p.Glu331Lys) results in a conservative amino acid change located in the DNA mismatch repair protein, S5 domain 2-like domain (IPR013507) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251340 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.991G>A has been reported in the literature in individuals diagnosed with breast cancer and medulloblastoma without evidence for causality (example: Zhang_2015 and Kwong_2020). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

The MLH1 c.991G>A variant is predicted to result in the amino acid substitution p.Glu331Lys. This variant has previously been reported as a variant of uncertain significance in a cohort of individuals with breast and/or ovarian cancer (Kwong et al. 2020. PubMed ID: 32068069, supplementary data) and in an individual with medulloblastoma (Zhang et al. 2015. PubMed ID: 26580448, supplementary data). This variant is reported in 0.0085% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-37061907-G-A) and is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/230317/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

This missense variant replaces glutamic acid with lysine at codon 331 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 reported for this variant. This variant has been reported in an individual with breast and/or ovarian cancer (PMID: 32068069) and an individual with medulloblastoma (PMID: 26580448). This variant has been identified in 6/282742 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 331 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 reported for this variant. This variant has been reported in an individual with breast and/or ovarian cancer (PMID: 32068069) and an individual with medulloblastoma (PMID: 26580448). This variant has been identified in 6/282742 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.