Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV001018550 | SCV001179802 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-14 | criteria provided, single submitter | clinical testing | The p.A299T variant (also known as c.895G>A), located in coding exon 6 of the NTHL1 gene, results from a G to A substitution at nucleotide position 895. The alanine at codon 299 is replaced by threonine, an amino acid with similar properties. This variant was detected in a single case from a large breast cancer cohort (Li N et al. NPJ Breast Cancer, 2021 May;7:52). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001036786 | SCV001200168 | uncertain significance | not provided | 2024-11-02 | criteria provided, single submitter | clinical testing | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 299 of the NTHL1 protein (p.Ala299Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 33980861). ClinVar contains an entry for this variant (Variation ID: 822844). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. |
| Baylor Genetics | RCV004569971 | SCV005053723 | uncertain significance | Familial adenomatous polyposis 3 | 2024-02-29 | criteria provided, single submitter | clinical testing | |
| Prevention |
RCV004751856 | SCV005346505 | uncertain significance | NTHL1-related disorder | 2024-07-24 | no assertion criteria provided | clinical testing | The NTHL1 c.895G>A variant is predicted to result in the amino acid substitution p.Ala299Thr. This variant has been observed in an individual from a large cohort of patients with breast cancer (Supplementary Table 2, Li. et al. 2021. PubMed ID: 33980861). This variant is reported in 0.00090% of alleles in individuals of European (Non-Finnish) descent in gnomAD and it has been interpreted as a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/822844/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |