Submissions for variant NM_000249.4(MLH1):c.2213G>A (p.Gly738Glu)

gnomAD frequency: 0.00007  dbSNP: rs148317871

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000767194	SCV000211122	uncertain significance	not provided	2023-02-16	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with polyposis and in patients with breast and/or ovarian cancer (Shirts et al., 2016; Cock-Rada et al., 2018; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 26845104, 28528518, 12799449, 20533529, 22753075, 31658756, 33471991, 30675060)
University of Washington Department of Laboratory Medicine, University of Washington	RCV000030221	SCV000266179	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Invitae	RCV000524281	SCV000284052	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 738 of the MLH1 protein (p.Gly738Glu). This variant is present in population databases (rs148317871, gnomAD 0.02%). This missense change has been observed in individual(s) with breast and/or ovarian cancer and colorectal polyposis and a family history of pancreatic cancer (PMID: 26845104, 28528518). ClinVar contains an entry for this variant (Variation ID: 36548). 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.
Counsyl	RCV000411992	SCV000488721	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-05-27	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000573289	SCV000662026	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-08	criteria provided, single submitter	clinical testing	The p.G738E variant (also known as c.2213G>A), located in coding exon 19 of the MLH1 gene, results from a G to A substitution at nucleotide position 2213. The glycine at codon 738 is replaced by glutamic acid, an amino acid with similar properties. This variant was detected in a Brazilian cohort of breast cancer patients (Urbina-Jara LK et al. Genes (Basel), 2019 10;10). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000160545	SCV000696152	uncertain significance	not specified	2022-08-08	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.2213G>A (p.Gly738Glu) results in a non-conservative amino acid change located in the DNA mismatch repair protein Mlh1, C-terminal domain (IPR032189) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.4e-05 in 282678 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2213G>A has been reported in the literature in one individual with polyposis who had first degree relative(s) with pancreatic cancer and in individual(s) affected with breast and/or ovarian cancer (Shirts_2016, Cock-Rada_2018, Dorling_2021). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome/HNPCC. At-least one co-occurrence with other pathogenic variant(s) has been observed at our laboratory (MSH2 c.1915C>T, p.His639Tyr), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: all have classified the variant as of uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000767194	SCV001134306	uncertain significance	not provided	2022-10-20	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.00016 (4/24974 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in an individual with pancreatic cancer and polyposis (PMID: 26845104 (2016)) and in an individual with breast and/or ovarian cancer (PMID: 28528518 (2017)). In a large scale breast cancer association study, the variant was observed in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Color Diagnostics, LLC DBA Color Health	RCV000573289	SCV001354157	uncertain significance	Hereditary cancer-predisposing syndrome	2023-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 738 of the MLH1 protein. Computational prediction tool 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 polyposis (PMID: 26845104), breast cancer (PMID: 33471991), and breast and/or ovarian cancer (PMID: 28528518). This variant has also been identified in 4/282678 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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000767194	SCV001471632	uncertain significance	not provided	2019-08-22	criteria provided, single submitter	clinical testing	The MLH1 c.2213G>A; p.Gly738Glu variant (rs148317871) is reported in the literature in an individual with polyposis and a family history of pancreatic cancer (Shirts 2016), and in an individual with hereditary breast and ovarian cancer syndrome (Cock-Rada 2018). This variant is also reported by multiple laboratories in the ClinVar database (Variation ID: 36548). It is found in the general population with a low overall allele frequency of 0.001% (4/282678 alleles) in the Genome Aggregation Database. The glycine at codon 738 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Due to limited information, the clinical significance of this variant is uncertain at this time. REFERENCES Cock-Rada AM et al. A multi-gene panel study in hereditary breast and ovarian cancer in Colombia. Fam Cancer. 2018 Jan;17(1):23-30. Shirts BH et al. Improving performance of multigene panels for genomic analysis of cancer predisposition. Genet Med. 2016 Oct;18(10):974-81.
Sema4, Sema4	RCV000573289	SCV002528728	uncertain significance	Hereditary cancer-predisposing syndrome	2021-04-12	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411992	SCV004018198	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
All of Us Research Program, National Institutes of Health	RCV000030221	SCV004843298	uncertain significance	Lynch syndrome	2023-02-24	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with glutamic acid at codon 738 of the MLH1 protein. Computational prediction tool 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 an individual affected with polyposis (PMID: 26845104) and an individual who underwent genetic testing for hereditary breast and ovarian cancer (PMID: 28528518). This variant has also been identified in 4/282678 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.