Submissions for variant NM_002878.4(RAD51D):c.144+3G>T

gnomAD frequency: 0.00001  dbSNP: rs761057565

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000529772	SCV000651716	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2025-01-14	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000563004	SCV000667147	likely benign	Hereditary cancer-predisposing syndrome	2018-03-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Color Diagnostics, LLC DBA Color Health	RCV000563004	SCV001346387	uncertain significance	Hereditary cancer-predisposing syndrome	2021-09-23	criteria provided, single submitter	clinical testing	This variant causes a G to T nucleotide substitution at the +3 position of intron 2 of the RAD51D gene. RNA functional studies have reported that this variant does not affect RNA splicing (PMID: 31642931). To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 18/282826 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001555608	SCV001777054	uncertain significance	not provided	2019-09-10	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In-silico analysis, which includes splice predictors and evolutionary conservation, is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; Also known as IVS3+3G>T; This variant is associated with the following publications: (PMID: 31642931)
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000529772	SCV001552820	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4		no assertion criteria provided	clinical testing	The RAD51D c.144+3G>T variant was not identified in the literature nor was it identified in the Cosmic, databases. The variant was identified in dbSNP (ID: rs761057565) as “NA”, ClinVar (classified uncertain significance by Invitae and Ambry Genetics) and in control databases in 17 of 277220 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include Other in 1 of 6466 chromosomes (freq: 0.0002) and East Asian in 16 of 18870 chromosomes (freq: 0.0008), while not observed in the African, Latino, European Non-Finnish, Ashkenazi Jewish, European Finnish, and South Asian populations. The c.144+3G>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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.