Submissions for variant NM_005732.4(RAD50):c.281T>C (p.Ile94Thr)

gnomAD frequency: 0.00004  dbSNP: rs768127412

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164812	SCV000215494	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-09	criteria provided, single submitter	clinical testing	The p.I94T variant (also known as c.281T>C), located in coding exon 3 of the RAD50 gene, results from a T to C substitution at nucleotide position 281. The isoleucine at codon 94 is replaced by threonine, an amino acid with similar properties. In a study of 52 unrelated women considered at risk for hereditary breast and ovarian cancer (HBOC) who previously tested negative for BRCA1/2 mutations, this alteration was detected in one patient whose breast tumor showed loss of heterozygosity (Grasel RS et al. Front Oncol, 2020 Oct;10:571330). This alteration has also been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535). This amino acid position is poorly 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 (formerly Invitae), Labcorp	RCV000164812	SCV000628226	uncertain significance	Hereditary cancer-predisposing syndrome	2024-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 94 of the RAD50 protein (p.Ile94Thr). This variant is present in population databases (rs768127412, gnomAD 0.02%). This missense change has been observed in individual(s) with personal or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 185400). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD50 protein function with a negative predictive value of 80%. 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.
GeneKor MSA	RCV000164812	SCV000822152	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001255536	SCV001431998	uncertain significance	not specified	2020-08-13	criteria provided, single submitter	clinical testing	Variant summary: RAD50 c.281T>C (p.Ile94Thr) results in a non-conservative amino acid change located in the Rad50/SbcC-type AAA domain (IPR038729) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251350 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome (4.4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.281T>C has been reported in the literature in one individual with personal of family history of breast and/or ovarian cancer (Tsaousis_2019). The report does not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Baylor Genetics	RCV003462149	SCV004207348	uncertain significance	Nijmegen breakage syndrome-like disorder	2023-09-05	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV003477611	SCV004220091	uncertain significance	not provided	2023-06-28	criteria provided, single submitter	clinical testing	In the published literature, the variant has been reported in an individual with a personal or family history of breast/ovarian cancer (PMID: 31159747 (2019), 33134171 (2020)). In a large scale breast cancer association study, the variant was observed in breast cancer cases as well as in control subjects (see LOVD (http://databases.lovd.nl/shared/genes/RAD50) and PMID: 33471991 (2021)). The frequency of this variant in the general population, 0.00016 (5/30608 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant.