ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.434A>G (p.Asn145Ser)

dbSNP: rs1553642117
Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000533987 SCV000625161 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2023-01-31 criteria provided, single submitter clinical testing In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 145 of the MLH1 protein (p.Asn145Ser). ClinVar contains an entry for this variant (Variation ID: 455437). This variant has not been reported in the literature in individuals affected with MLH1-related conditions. This variant is not present in population databases (gnomAD no frequency).
Ambry Genetics RCV002330820 SCV002632198 uncertain significance Hereditary cancer-predisposing syndrome 2021-04-08 criteria provided, single submitter clinical testing The p.N145S variant (also known as c.434A>G), located in coding exon 5 of the MLH1 gene, results from an A to G substitution at nucleotide position 434. The asparagine at codon 145 is replaced by serine, an amino acid with highly similar properties. This variant was reported in 2/60,466 breast cancer cases and in 0/53,461 controls (Dorling et al. N Engl J Med, 2021 02;384:428-439). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Baylor Genetics RCV003470708 SCV004192987 uncertain significance Colorectal cancer, hereditary nonpolyposis, type 2 2023-06-12 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004003721 SCV004837521 uncertain significance Lynch syndrome 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces asparagine with serine at codon 145 of the MLH1 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MLH1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.