Submissions for variant NM_000249.4(MLH1):c.1344G>T (p.Glu448Asp)

gnomAD frequency: 0.00001  dbSNP: rs587779952

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212536	SCV000149366	uncertain significance	not provided	2023-10-24	criteria provided, single submitter	clinical testing	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 individuals with a personal and family history of colorectal cancer, as well as in individuals with breast cancer (PMID: 33471991, 25559809, 32658311); This variant is associated with the following publications: (PMID: 32658311, 33471991, 22753075, 25559809)
Ambry Genetics	RCV000115457	SCV000215076	likely benign	Hereditary cancer-predisposing syndrome	2022-07-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl	RCV000412424	SCV000487997	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2015-12-18	criteria provided, single submitter	clinical testing
Invitae	RCV000545514	SCV000625057	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2023-12-13	criteria provided, single submitter	clinical testing	This sequence change replaces glutamic acid, which is acidic and polar, with aspartic acid, which is acidic and polar, at codon 448 of the MLH1 protein (p.Glu448Asp). This variant is present in population databases (rs587779952, gnomAD 0.006%). This missense change has been observed in individual(s) with colorectal cancer (PMID: 25559809). ClinVar contains an entry for this variant (Variation ID: 127612). 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) performed at Invitae indicates that this missense variant is not expected to disrupt MLH1 protein function with a negative predictive value of 95%. 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	RCV000115457	SCV000684737	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-07	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 448 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with colon cancer (PMID 25559809). This variant has been identified in 4/251190 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.
Mendelics	RCV000412424	SCV001136409	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2019-05-28	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115457	SCV002528640	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-26	criteria provided, single submitter	curation
Mayo Clinic Laboratories, Mayo Clinic	RCV000212536	SCV002542035	uncertain significance	not provided	2022-01-04	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002505032	SCV002815510	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2021-12-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000412424	SCV004018135	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	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.
Baylor Genetics	RCV000412424	SCV004195028	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-10-26	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212536	SCV004220065	uncertain significance	not provided	2023-04-25	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000016 (4/251190 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in individuals with breast cancer (PMIDs: 32658311 (2021) and 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MLH1)) and colon cancer (PMID: 25559809 (2015)). In addition, this variant has been reported in a healthy control individual (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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.
All of Us Research Program, National Institutes of Health	RCV003997261	SCV004840993	uncertain significance	Lynch syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with aspartic acid at codon 448 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 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 colon cancer in the literature (PMID 25559809). This variant has been identified in 4/251190 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.