Submissions for variant NM_000249.4(MLH1):c.1040C>A (p.Thr347Asn)

gnomAD frequency: 0.00017  dbSNP: rs201541505

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075098	SCV000106090	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000587202	SCV000149358	uncertain significance	not provided	2018-03-17	criteria provided, single submitter	clinical testing	This variant is denoted MLH1 c.1040C>A at the cDNA level, p.Thr347Asn (T347N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as benign based on a multifactorial model that incorporates in silico models and segregation within families; however, this data is not available for independent review (Thompson 2013, Thompson 2014). MLH1 Thr347Asn was observed at an allele frequency of 0.013% (14/101,232) in individuals of European ancestry in large population cohorts (Lek 2016). MLH1 Thr347Asn is not located in a known functional domain. In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available information, it is unclear whether MLH1 Thr347Asn is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae	RCV000524221	SCV000153962	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000115449	SCV000212876	benign	Hereditary cancer-predisposing syndrome	2014-12-13	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000212529	SCV000539652	uncertain significance	not specified	2016-12-14	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant is in the second base of exon 12 (of 19 exons). This variant is present in ExAC and gnomAD at a MaxMAF of 0.01% (15 alleles). It is classified in ClinVar as Benign by Ambry and an expert panel (InSiGHT - 3 stars) and as VUS by Invitae and GeneDx. It has not been reported in affected individuals but was seen in the Invitae database in a patient who had another PMS2 variant that was likely to explain disease.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000587202	SCV000601343	uncertain significance	not provided	2020-08-26	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212529	SCV000696093	likely benign	not specified	2019-04-18	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1040C>A (p.Thr347Asn) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.3e-05 in 206178 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLH1 causing Lynch Syndrome (7.3e-05 vs 0.00071), allowing no conclusion about variant significance. c.1040C>A has been reported in the literature in at-least one proband affected with colorectal cancer (Thompson_2013). This report(s) does not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Additionally, it was reported in a patient with sporadic etiology for colorectal cancer as evidenced by BRAF mutation positivity, high MSI, and a negative MLH1 and PMS2 staining by IHC (van der Klift_2016). BRAF mutation and MLH1 promoter hypermethylation have been reported as strong predictors of a negative germline MMR mutational status (Parsons_2012, PMID 22368298). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Additionally, one submission indicates the variant co-occurred with a pathogenic PMS2 variant (variant not indicated). In addition, an expert panel submitter, InSiGHT, and another submitter (evaluation before 2014) have classified the variant as benign. Therefore, based on the evidence outlined above, the variant was classified as likely benign.
Color Diagnostics, LLC DBA Color Health	RCV000115449	SCV000910763	likely benign	Hereditary cancer-predisposing syndrome	2016-07-14	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115449	SCV002528616	benign	Hereditary cancer-predisposing syndrome	2020-10-19	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212529	SCV002552489	likely benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000212529	SCV001742303	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000212529	SCV001797959	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000212529	SCV001956507	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000212529	SCV002034317	benign	not specified		no assertion criteria provided	clinical testing