Submissions for variant NM_000249.4(MLH1):c.991G>A (p.Glu331Lys)

gnomAD frequency: 0.00003  dbSNP: rs550914672

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213338	SCV000273824	uncertain significance	Hereditary cancer-predisposing syndrome	2022-09-16	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000222012	SCV000279886	uncertain significance	not provided	2018-02-02	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.991G>A at the cDNA level, p.Glu331Lys (E331K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MLH1 Glu331Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the N-terminal ATPase domain (Andersen 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MLH1 Glu331Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000537429	SCV000625216	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-18	criteria provided, single submitter	clinical testing	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.
Color Diagnostics, LLC DBA Color Health	RCV000213338	SCV000684889	uncertain significance	Hereditary cancer-predisposing syndrome	2023-02-21	criteria provided, single submitter	clinical testing	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.
Division of Medical Genetics, University of Washington	RCV001257463	SCV001434263	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-11-25	criteria provided, single submitter	clinical testing	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
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000222012	SCV001470546	uncertain significance	not provided	2021-08-27	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818518	SCV002066753	uncertain significance	not specified	2020-12-31	criteria provided, single submitter	clinical testing	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.
Sema4, Sema4	RCV000213338	SCV002528793	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-18	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001818518	SCV002570540	uncertain significance	not specified	2022-07-11	criteria provided, single submitter	clinical testing	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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818518	SCV004024904	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003417783	SCV004115320	uncertain significance	MLH1-related disorder	2023-10-12	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV003997823	SCV004840938	uncertain significance	Lynch syndrome	2023-12-18	criteria provided, single submitter	clinical testing	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.