Submissions for variant NM_005732.4(RAD50):c.281T>C (p.Ile94Thr) (rs768127412)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164812	SCV000215494	uncertain significance	Hereditary cancer-predisposing syndrome	2018-12-04	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. 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.
Invitae	RCV000164812	SCV000628226	uncertain significance	Hereditary cancer-predisposing syndrome	2020-09-17	criteria provided, single submitter	clinical testing	This sequence change replaces isoleucine with threonine at codon 94 of the RAD50 protein (p.Ile94Thr). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and threonine. This variant is present in population databases (rs768127412, ExAC 0.02%). This variant has been observed in an individual with personal or family history of breast and/or ovarian cancer (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 185400). 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.