Submissions for variant NM_000249.4(MLH1):c.42A>C (p.Thr14=)

gnomAD frequency: 0.00007  dbSNP: rs369737664

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081345	SCV000166255	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000212511	SCV000170302	benign	not specified	2014-05-08	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	RCV000126779	SCV000213203	likely benign	Hereditary cancer-predisposing syndrome	2014-07-03	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	RCV000126779	SCV000684829	likely benign	Hereditary cancer-predisposing syndrome	2015-04-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000585926	SCV000696164	likely benign	not provided	2017-06-23	criteria provided, single submitter	clinical testing	Variant summary: The MLH1 c.42A>C (p.Thr14Thr) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 11/121284 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.001271 (11/8654). This frequency is about 2 times the estimated maximal expected allele frequency of a pathogenic MLH1 variant (0.0007105), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported as a confirmed germline variant in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is currently classified as likely benign.
Illumina Laboratory Services, Illumina	RCV001147828	SCV001308679	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 2	2017-04-28	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000585926	SCV001471824	likely benign	not provided	2020-08-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000212511	SCV002071026	likely benign	not specified	2018-04-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126779	SCV002528745	likely benign	Hereditary cancer-predisposing syndrome	2021-08-17	criteria provided, single submitter	curation
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492536	SCV004240756	likely benign	Breast and/or ovarian cancer	2022-09-23	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003975092	SCV004789623	likely benign	MLH1-related disorder	2020-03-10	criteria provided, single submitter	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
All of Us Research Program, National Institutes of Health	RCV003997404	SCV004835217	likely benign	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358331	SCV001554033	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The MLH1 p.Thr14= variant was not identified in the literature nor was it identified in the GeneInsight-COGR, MutDB, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, or Mismatch Repair Genes Variant Database. The variant was identified in dbSNP (ID: rs369737664) “With Likely benign allele”, ClinVar (classified benign by Invitae and GeneDx, and likely benign by Ambry Genetics), Clinvitae (4x), Insight Hereditary Tumors Database (8X), and in control databases in 27 of 277218 chromosomes at a frequency of 0.000097 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 2 of 6466 chromosomes (freq: 0.0003), and East Asian in 25 of 18870 chromosomes (freq: 0.0013), while the variant was not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The p.Thr14= 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 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.