Submissions for variant NM_000249.4(MLH1):c.955G>A (p.Glu319Lys)

gnomAD frequency: 0.00006  dbSNP: rs63750796

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656859	SCV000149398	uncertain significance	not provided	2022-12-08	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate no damaging effect in a methylation tolerance assay (Bouvet et al., 2019); This variant is associated with the following publications: (PMID: 18566915, 26845104, 25871441, 27601186, 27498913, 28503720, 25186627, 31391288, 31187078, 22753075, 30998989, 20373145)
Ambry Genetics	RCV000115489	SCV000185511	likely benign	Hereditary cancer-predisposing syndrome	2019-03-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000524325	SCV000260533	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
University of Washington Department of Laboratory Medicine, University of Washington	RCV000075945	SCV000266184	uncertain significance	Lynch syndrome	2015-11-20	criteria provided, single submitter	clinical testing
Counsyl	RCV000410221	SCV000489392	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2016-09-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212528	SCV000601418	uncertain significance	not specified	2017-05-10	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115489	SCV000684885	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-15	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 319 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). A functional study has shown the mutant protein to be functional in a methylation tolerance-based assay (PMID: 30998989). This variant has been reported in individuals affected with or suspected of having Lunch syndrome (PMID: 18566915, 20373145, 27601186), in individuals affected with breast cancer (PMID: 25186627, 26845104, 28503720; DOI: 10.1101/2021.04.15.21255554v2) and in an individual affected with sarcoma (PMID: 27498913). This variant has been identified in 18/282792 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.
Fulgent Genetics, Fulgent Genetics	RCV000764484	SCV000895555	uncertain significance	Mismatch repair cancer syndrome 1; Muir-Torré syndrome; Colorectal cancer, hereditary nonpolyposis, type 2	2018-10-31	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212528	SCV002552448	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000656859	SCV002821175	uncertain significance	not provided	2022-10-01	criteria provided, single submitter	clinical testing	MLH1: PP3, BS3:Supporting
Myriad Genetics, Inc.	RCV000410221	SCV004018142	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-14	criteria provided, single submitter	clinical testing	This variant is considered 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]. This variant has been observed in conjunction with multiple pathogenic variants, reducing the likelihood this variant itself is pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656859	SCV004226064	uncertain significance	not provided	2022-12-09	criteria provided, single submitter	clinical testing	PP3
Mendelics	RCV003492419	SCV004232564	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	RCV000410221	SCV004807654	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2024-03-29	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000075945	SCV004840930	uncertain significance	Lynch syndrome	2023-12-13	criteria provided, single submitter	clinical testing	This missense variant replaces glutamic acid with lysine at codon 319 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). A functional study has shown the mutant protein to be functional in a methylation tolerance-based assay (PMID: 30998989). This variant has been reported in individuals affected with or suspected of having Lunch syndrome (PMID: 18566915, 20373145, 27601186), in individuals affected with breast cancer (PMID: 25186627, 26845104, 28503720; DOI: 10.1101/2021.04.15.21255554v2) and in an individual affected with sarcoma (PMID: 27498913). This variant has been identified in 18/282792 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.
Pathway Genomics	RCV000144597	SCV000189924	uncertain significance	Lynch syndrome 1	2014-07-24	no assertion criteria provided	clinical testing
GenomeConnect, ClinGen	RCV000656859	SCV000986701	not provided	not provided		no assertion provided	phenotyping only	Variant interpretted as Uncertain significance and reported on 11/29/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357697	SCV001553241	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MLH1 p.Glu319Lys variant was identified in 4 of 7680 proband chromosomes (frequency: 0.0005) from individuals or families with Lynch syndrome or breast cancer (Lagerstedt-Robinson 2016, Nilbert 2009, Shirts 2015, Tung 2015). The variant was also identified in dbSNP (ID: rs63750796) as "With Pathogenic, other allele", ClinVar (classified a likely benign by Ambry Genetics; as uncertain significance by Invitae, GeneDx, Counsyl and five other submitters), and in UMD-LSDB (1x as unclassified variant).. The variant was identified in control databases in 17 of 277130 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 24036 chromosomes (freq: 0.00004), Latino in 1 of 34420 chromosomes (freq: 0.00003), European in 15 of 126622 chromosomes (freq: 0.0001), while the variant was not observed in the Other, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Glu319 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000656859	SCV001977705	uncertain significance	not provided		no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000656859	SCV001978466	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003915040	SCV004729608	uncertain significance	MLH1-related disorder	2024-01-08	no assertion criteria provided	clinical testing	The MLH1 c.955G>A variant is predicted to result in the amino acid substitution p.Glu319Lys. This variant has been reported in individuals with breast cancer (Shirts et al. Table S1. 2016. PubMed ID: 26845104; Rummel et al. 2017. PubMed ID: 28503720; Tung et al. 2015. PubMed ID: 25186627, supplementary data) and two individuals referred for diagnostic Lynch syndrome testing (Nilbert et al. 2009. PubMed ID: 18566915; Lagerstedt-Robinson et al. 2016. PubMed ID: 27601186). A different nucleotide variant predicted to cause the same amino acid substitution (c.954_955delCGinsTA, p.Glu319Lys) was reported in an individual with a personal and family history of colorectal cancer (Tunca et al. 2010. PubMed ID: 20373145). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from likely benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/90452/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.