Submissions for variant NM_002878.4(RAD51D):c.932T>A (p.Ile311Asn)

gnomAD frequency: 0.00041  dbSNP: rs145309168

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656967	SCV000149731	uncertain significance	not provided	2021-05-03	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22986143, 26824983, 32019284, 18951446, 28961279, 29263802, 29522266, 29338689, 30111881, 31159747, 31514334, 32255556, 32566746, 33785725, 32068069)
Ambry Genetics	RCV000115822	SCV000185850	likely benign	Hereditary cancer-predisposing syndrome	2020-04-23	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000233793	SCV000287734	benign	Breast-ovarian cancer, familial, susceptibility to, 4	2024-02-01	criteria provided, single submitter	clinical testing
Counsyl	RCV000233793	SCV000488794	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2016-10-11	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656967	SCV000602171	likely benign	not provided	2021-01-22	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115822	SCV000686502	likely benign	Hereditary cancer-predisposing syndrome	2019-12-11	criteria provided, single submitter	clinical testing
GeneKor MSA	RCV000115822	SCV000822186	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Mendelics	RCV003492497	SCV000839169	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
Cancer Genomics Group, Japanese Foundation For Cancer Research	RCV000709427	SCV001193724	uncertain significance	Hereditary breast ovarian cancer syndrome	2019-05-01	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000656967	SCV001250268	likely benign	not provided	2024-08-01	criteria provided, single submitter	clinical testing	RAD51D: BP4, BS1
Genetic Services Laboratory, University of Chicago	RCV001818279	SCV002072437	uncertain significance	not specified	2020-05-11	criteria provided, single submitter	clinical testing	DNA sequence analysis of the RAD51D gene demonstrated a sequence change, c.932T>A, in exon 10 that results in an amino acid change, p.Ile311Asn. This sequence change has been described in the gnomAD database with a frequency of 0.43% in the East Asian sub-population (dbSNP rs145309168). The p.Ile311Asn change has been reported in individuals with ovarian, breast, and peritoneal cancers (PMIDs: 30111881, 26824983, 22986143). Additionally, two different amino acid changes at the same location, p.Ile311Val and p.Ile311Met, have been reported for predisposition to hereditary breast and ovarian cancer (PMID: 31159747). The p.Ile311Asn change affects a highly conserved amino acid residue located in a domain of the RAD51D protein that is not known to be functional. The p.Ile311Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile311Asn change remains unknown at this time.
Sema4, Sema4	RCV000115822	SCV002527053	likely benign	Hereditary cancer-predisposing syndrome	2021-07-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV001818279	SCV002550910	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003149804	SCV003838852	likely benign	Breast and/or ovarian cancer	2021-06-11	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000233793	SCV004017732	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000656967	SCV005412694	uncertain significance	not provided	2024-06-17	criteria provided, single submitter	clinical testing	BS1
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354391	SCV001548997	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Ile311Asn variant was identified in 6 of 1426 proband chromosomes (frequency: 0.0042) from individuals or families with breast and ovarian cancer (Lin 2016, Wickramanayake 2012, Wong 2016). The variant was also identified in dbSNP (ID: rs145309168) as “With Uncertain significance, other allele”, ClinVar (as likely benign by Invitae and as uncertain significance by GeneDx, Ambry Genetics and Counsyl), and Clinvitae databases. The variant was not identified in the Cosmic database. The variant was identified in control databases in 122 of 277230 chromosomes at a frequency of 0.00044 in the following populations: European (Non-Finnish) in 26 of 126716 chromosomes (freq. 0.0002), East Asian in 83 (1 homozygous) of 18868 chromosomes (freq. 0.004), European (Finnish) in 2 of 25794 chromosomes (freq. 0.00008) and South Asian in 9 of 30782 chromosomes (freq. 0.0003), and Other in 2 of 6468 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant is located in the ATPase domain of the RAD51D protein (Kim 2011). The p.Ile311Asn residue is conserved in mammals but not in more distantly related organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) 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. This variant is classified as a variant of uncertain significance.
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000656967	SCV002034333	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656967	SCV002037488	uncertain significance	not provided		no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004751266	SCV005351208	uncertain significance	RAD51D-related disorder	2024-08-09	no assertion criteria provided	clinical testing	The RAD51D c.932T>A variant is predicted to result in the amino acid substitution p.Ile311Asn. This variant has been reported in over 25 individuals with a personal or family history of breast and/or ovarian cancer (Lin et al. 2016. PubMed ID: 26824983; Table 2 Wong et al. 2016. PubMed ID: 29263802; Supp. Table 1 in Kwong et al. 2020. PubMed ID: 32068069; Hauke et al. 2018. PubMed ID: 29522266; Gervas et al. 2021. PubMed ID: 33785725; Table S5. Tsaousis et al. 2019. PubMed ID: 31159747). This variant has also been reported in individuals with a personal or family history of ovarian cancer (Table 2, Wickramanayake et al. 2012. PubMed ID: 22986143; Konstanta et al. 2018. PubMed ID: 301118810), an individual with gastric cancer (Tedaldi et al. 2019. PubMed ID: 31514334), and an individual with pancreatic ductal adenocarcinoma (Supp. Table 2 Cremin et al. 2020. PubMed ID: 32255556). This variant is reported in 0.43% of alleles in individuals of East Asian descent in gnomAD, including 1 homozygote. The c.932T>A variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127896/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.