Submissions for variant NM_058216.3(RAD51C):c.1008A>G (p.Thr336=)

gnomAD frequency: 0.00001  dbSNP: rs1057521598

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000567794	SCV000663773	likely benign	Hereditary cancer-predisposing syndrome	2016-03-18	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Invitae	RCV000648289	SCV000770103	likely benign	Fanconi anemia complementation group O	2024-01-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000567794	SCV000913080	likely benign	Hereditary cancer-predisposing syndrome	2018-07-17	criteria provided, single submitter	clinical testing
GeneDx	RCV001764646	SCV002000549	uncertain significance	not provided	2021-04-15	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV002291669	SCV002584610	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 3	2022-09-01	criteria provided, single submitter	clinical testing	The RAD51C c.1008A>G (p.Thr336=) synonymous change is absent in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). Algorithms that predict the impact of sequence changes on splicing indicate that this change may activate a cryptic donor splice site. RNA data supports this prediction and desmontrates alternative splicing that results in the removal of six amino acids in exon 8 while preserving the reading frame (internal data). This variant is absent in a database of women older than 70 years of age who have never had cancer (https://whi.color.com/). To our knowledge, this variant has not been reported in the literature in individuals with hereditary breast and ovarian cancer syndrome or Fanconi anemia. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354176	SCV001548723	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51C p.Thr336= variant was not identified in the literature nor was it identified in the following databases: dbSNP, Cosmic, MutDB, or LOVD 3.0. The variant was identified in ClinVar (classified as likely benign by Ambry Genetics and Invitae). The variant was not identified in the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Thr336= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence, although 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.