Submissions for variant NM_000249.4(MLH1):c.1128T>C (p.Asp376=)

gnomAD frequency: 0.00005  dbSNP: rs267607824

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000075113	SCV000106105	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Invitae	RCV001080774	SCV000259719	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000410805	SCV000488560	likely benign	Colorectal cancer, hereditary nonpolyposis, type 2	2016-04-28	criteria provided, single submitter	clinical testing
GeneDx	RCV000442515	SCV000513623	benign	not specified	2015-07-15	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000569167	SCV000669527	likely benign	Hereditary cancer-predisposing syndrome	2015-02-19	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	RCV000569167	SCV000684716	likely benign	Hereditary cancer-predisposing syndrome	2016-03-30	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000759078	SCV000888172	benign	not provided	2018-05-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000442515	SCV000917643	benign	not specified	2018-04-13	criteria provided, single submitter	clinical testing	Variant summary: MLH1 c.1128T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 1.55 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLH1 causing Lynch Syndrome phenotype (0.00071), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1128T>C has been reported in the literature in individuals affected with Lynch Syndrome, however 9 out of the reported 18 families with c.1128T>C (Asp376) also had pathogenic mutations in MLH1, MSH2 or MSH6 (Shin_2004), strongly supporting the benign nature of this variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Sema4, Sema4	RCV000569167	SCV002528623	likely benign	Hereditary cancer-predisposing syndrome	2021-08-25	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410805	SCV004018192	benign	Colorectal cancer, hereditary nonpolyposis, type 2	2023-03-15	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.
All of Us Research Program, National Institutes of Health	RCV000075113	SCV004840959	likely benign	Lynch syndrome	2023-11-30	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000759078	SCV001548738	likely benign	not provided		no assertion criteria provided	clinical testing	MLH1, EXON 12, c.1128T>C, p.Asp376=, Heterozygous, Likely benign The MLH1 p.Asp376= variant was identified in 18 of 282 proband chromosomes (frequency: 0.06) from individuals or families with Lynch syndrome and was present in 12 of 368 control chromosomes (frequency: 0.03) from healthy individuals (Shin 2004). The variant was also identified in the following databases: dbSNP (ID: rs267607824) as "With Likely benign allele", ClinVar (3x likely benign, 3x benign including review by expert panel InSiGHT), Clinvitae, Mismatch Repair Genes Variant Database, and the Insight Hereditary Tumors Database (1x, not pathogenic). The variant was not identified in GeneInsight-COGR, Cosmic, MutDB, UMD-LSDB, or the Zhejiang Colon Cancer Database. The variant was identified in control databases in 20 of 276984 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include East Asian in 20 of 18854 chromosomes (freq: 0.001), while the variant was not observed in the African, Other, Latino, European, Ashkenazi Jewish, Finnish, and South Asian populations. A study by Shin 2004 found no statistically significant difference in frequency between Lynch syndrome patients and controls for this variant, and listed it as a polymorphism. The p.Asp376= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.