Submissions for variant NM_001040108.2(MLH3):c.3751C>T (p.Arg1251Trp)

gnomAD frequency: 0.00001  dbSNP: rs754799700

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001121760	SCV001203531	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 7	2023-02-13	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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1251 of the MLH3 protein (p.Arg1251Trp). This variant is present in population databases (rs754799700, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MLH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 838432).
Illumina Laboratory Services, Illumina	RCV001121760	SCV001280407	uncertain significance	Colorectal cancer, hereditary nonpolyposis, type 7	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Ambry Genetics	RCV002348347	SCV002621277	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-08	criteria provided, single submitter	clinical testing	The p.R1251W variant (also known as c.3751C>T), located in coding exon 7 of the MLH3 gene, results from a C to T substitution at nucleotide position 3751. The arginine at codon 1251 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is conserved. 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003321786	SCV004027518	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing