Submissions for variant NM_000249.4(MLH1):c.80G>A (p.Arg27Gln)

gnomAD frequency: 0.00005  dbSNP: rs138705565

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000197307	SCV000254372	uncertain significance	Hereditary nonpolyposis colorectal neoplasms	2024-01-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 27 of the MLH1 protein (p.Arg27Gln). This variant is present in population databases (rs138705565, gnomAD 0.004%). This missense change has been observed in individual(s) with colorectal cancer or breast cancer (PMID: 25503501, 30729418). ClinVar contains an entry for this variant (Variation ID: 216337). 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 expected to disrupt MLH1 protein function with a positive predictive value of 80%. 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.
GeneDx	RCV000587717	SCV000279261	uncertain significance	not provided	2023-07-03	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 colorectal cancer or breast cancer (Maxwell et al., 2014; Clarke et al., 2019); This variant is associated with the following publications: (PMID: 22949387, 22290698, 25503501, 30729418, 22753075, 32123317)
Ambry Genetics	RCV000573727	SCV000662012	likely benign	Hereditary cancer-predisposing syndrome	2019-04-19	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.
Color Diagnostics, LLC DBA Color Health	RCV000573727	SCV000689923	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 27 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 individuals affected with breast cancer (PMID: 25503501) and Lynch syndrome (PMID: 30729418). The individual affected with Lynch syndrome also carried a pathogenic variant in MLH1 that could explain the observed phenotype. This variant has been identified in 5/282624 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000587717	SCV000696182	uncertain significance	not provided	2017-08-09	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.80G>A (p.Arg27Gln) variant involves the alteration of a conserved nucleotide, resulting in a missense change in the histidine kinase-like ATPase, C-terminal domain (InterPro). 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0000165 (2/121156 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105). The variant has been reported in a patient with early onset breast cancer without strong evidence for or against pathogenicity (Maxwell_Genet Med_2014). In addition, multiple clinical diagnostic laboratories have classified this variant as one of uncertain significance. Taken together, this variant is classified as a VUS.
Counsyl	RCV000662868	SCV000785757	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-11-20	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587717	SCV000889404	uncertain significance	not provided	2019-03-21	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000662868	SCV004018096	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-13	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Baylor Genetics	RCV000662868	SCV004190606	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2023-09-10	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000573727	SCV004228104	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-05	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997011	SCV004835231	uncertain significance	Lynch syndrome	2023-11-28	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 27 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 individuals affected with breast cancer (PMID: 25503501) and Lynch syndrome (PMID: 30729418). The individual affected with Lynch syndrome also carried a pathogenic variant in MLH1 that could explain the observed phenotype. This variant has been identified in 5/282624 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.