Submissions for variant NM_002878.4(RAD51D):c.904-3C>T

gnomAD frequency: 0.00018  dbSNP: rs45478491

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000212974	SCV000171279	benign	not specified	2014-02-26	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000130350	SCV000185201	likely benign	Hereditary cancer-predisposing syndrome	2018-09-19	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	RCV000233123	SCV000287731	likely benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000233123	SCV000488842	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-07-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000130350	SCV000691378	likely benign	Hereditary cancer-predisposing syndrome	2016-04-11	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679543	SCV000806591	likely benign	not provided	2017-12-06	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212974	SCV000918141	benign	not specified	2021-10-25	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.904-3C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. Experimental evidence supports these predictions indicating the variant has no effect on splicing (Casadei_2019). The variant allele was found at a frequency of 0.00024 in 253596 control chromosomes, predominantly at a frequency of 0.00044 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3.5-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.904-3C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, Lynch Syndrome and pancreatic ductal adenocarcinoma (Osher_2012, Tung_2015, Yurgelun_2015, Chaffee_2018), however it was also observed in controls (Loveday_2011). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Six ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign and five ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000679543	SCV001134808	likely benign	not provided	2022-11-04	criteria provided, single submitter	clinical testing
Mendelics	RCV000233123	SCV001140405	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000679543	SCV001747873	likely benign	not provided	2021-07-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV000233123	SCV001934383	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2021-01-05	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000130350	SCV002527050	likely benign	Hereditary cancer-predisposing syndrome	2021-07-02	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212974	SCV002550911	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000233123	SCV004017731	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2023-04-06	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
King Laboratory, University of Washington	RCV000212974	SCV001251346	benign	not specified	2019-09-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354829	SCV001549539	likely benign	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D c.904-3C>T variant was identified in 3 of 9008 proband chromosomes (frequency: 0.0003) from individuals or families with colorectal, breast and ovarian cancer and was present in 1 of 2120 control chromosomes (frequency: 0.004) from healthy individuals (Yurgelun 2015, Osher 2012, Tung 2015, Loveday 2011). The variant was identified in dbSNP (rs45478491) as “with uncertain significance allele” and ClinVar (classified as likely benign by Ambry Genetics, Color and 2 other submitters and uncertain significance by Invitae, Counsyl and 1 other submitter and benign by GeneDx). The variant was identified in control databases in 63 of 277,232 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 4 of 24,038 chromosomes (freq: 0.0002), Other in 2 of 6468 chromosomes (freq: 0.0003), Latino in 7 of 34,420 chromosomes (freq: 0.0002), European in 50 of 126,710 chromosomes (freq: 0.0004), but was not observed in the Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The c.904-3C>T variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. The variant occurs at a non-conserved nucleotide and 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.