ClinVar Miner

Submissions for variant NM_000249.3(MLH1):c.42A>C (p.Thr14=) (rs369737664)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001081345 SCV000166255 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-06 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: 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 Health, Inc 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 Clinical Services Laboratory,Illumina RCV001147828 SCV001308679 uncertain significance Lynch syndrome II 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 RCV001285405 SCV001471824 likely benign none provided 2020-08-25 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.

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