ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.221A>T (p.Asp74Val)

gnomAD frequency: 0.00001  dbSNP: rs751894165
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000460878 SCV000543579 benign Hereditary nonpolyposis colorectal neoplasms 2025-01-26 criteria provided, single submitter clinical testing
GeneDx RCV000522233 SCV000617961 uncertain significance not provided 2021-08-20 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 22753075)
Color Diagnostics, LLC DBA Color Health RCV000774691 SCV000908602 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-22 criteria provided, single submitter clinical testing
Ambry Genetics RCV000774691 SCV001175591 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-23 criteria provided, single submitter clinical testing The p.D74V variant (also known as c.221A>T), located in coding exon 3 of the MLH1 gene, results from an A to T substitution at nucleotide position 221. The aspartic acid at codon 74 is replaced by valine, an amino acid with highly dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003476023 SCV004195033 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-10-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000522233 SCV005877490 uncertain significance not provided 2024-04-25 criteria provided, single submitter clinical testing The MLH1 c.221A>T; p.Asp74Val variant (rs751894165, ClinVar Variation ID: 405401), to our knowledge, is not reported in the medical literature in MLH1-related conditions. This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.624). Due to limited information, the clinical significance of this variant is uncertain at this time.
Myriad Genetics, Inc. RCV003476023 SCV005897176 likely benign Colorectal cancer, hereditary nonpolyposis, type 2 2024-11-18 criteria provided, single submitter clinical testing This variant is considered likely 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: 27363726].

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