Submissions for variant NM_005732.4(RAD50):c.379G>A (p.Val127Ile)

gnomAD frequency: 0.00146  dbSNP: rs28903086

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000590280	SCV000149869	uncertain significance	not provided	2014-02-21	criteria provided, single submitter	clinical testing	RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.379G>A at the cDNA level and p.Val127Ile (V127I) at the protein level, and results in the change of a Valine to a Isoleucine (GTC>ATC). RAD50 Val127Ile has been reported in two individuals with breast cancer in British studies and in two individuals with laryngeal cancer in a Polish study, but was also detected in at least five healthy controls (Tommiska 2006, Mosor 2010, Mosor 2013, Ziolkowska-Suchanek 2013). RAD50 Val127Ile was observed with an allele frequency of 0.1% in 1000 Genomes and at 0.2% and 0.05% in European and African Americans in the NHLBI Exome Sequencing Project respectively, indicating it is not a common benign variant in these populations. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is highly conserved throughout evolution, and is not located in a known functional domain. In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. At a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Ambry Genetics	RCV000115960	SCV000183854	benign	Hereditary cancer-predisposing syndrome	2014-07-11	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000115960	SCV000253469	benign	Hereditary cancer-predisposing syndrome	2024-01-31	criteria provided, single submitter	clinical testing
Counsyl	RCV000409627	SCV000488865	uncertain significance	Nijmegen breakage syndrome-like disorder	2016-07-07	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000590280	SCV000698654	benign	not provided	2016-08-29	criteria provided, single submitter	clinical testing	Variant summary: The RAD50 c.379G>A (p.Val127Ile) variant involves the alteration of a conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant. This variant was found in 205/124248 control chromosomes (1 homozygote) at a frequency of 0.0016499, which is approximately 26 times the estimated maximal expected allele frequency of a pathogenic RAD50 variant (0.0000625), suggesting this variant is likely a benign polymorphism. This variant has been reported from case-control studies in literature. In a large case-control study, this variant was not associated with increased risk for breast cancer (Haiman_2013). 1/3 clinical diagnostic laboratories in ClinVar has classified this variant as likely benign. Taken together, this variant is classified as Benign.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000590280	SCV002009648	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV001818283	SCV002069722	benign	not specified	2021-06-22	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000409627	SCV002538517	benign	Nijmegen breakage syndrome-like disorder	2020-10-09	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV000590280	SCV004161371	likely benign	not provided	2024-05-01	criteria provided, single submitter	clinical testing	RAD50: BS2