Total submissions: 4
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, |
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. |