ClinVar Miner

Submissions for variant NM_000249.4(MLH1):c.1504A>G (p.Asn502Asp)

dbSNP: rs2125902825
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV004945055 SCV005448537 uncertain significance Hereditary cancer-predisposing syndrome 2024-12-04 criteria provided, single submitter clinical testing The p.N502D variant (also known as c.1504A>G), located in coding exon 13 of the MLH1 gene, results from an A to G substitution at nucleotide position 1504. The asparagine at codon 502 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001355433 SCV001550316 uncertain significance Carcinoma of colon no assertion criteria provided clinical testing The MLH1 p.Asn502Asp variant was not identified in the literature nor in dbSNP, ClinVar, ClinVar, Cosmic, UMD-LSDB, Insight Colon Cancer Gene Variant Database, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, Insight Hereditary Tumors Database, the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project or the Exome Aggregation Consortium (August 8th 2016) control databases. The p.Asn502 residue is not conserved in mammals and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest the Asp variant having a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance.

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