Submissions for variant NM_002878.4(RAD51D):c.137C>G (p.Ser46Cys)

gnomAD frequency: 0.00010  dbSNP: rs587780102

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000656964	SCV000149717	uncertain significance	not provided	2023-06-22	criteria provided, single submitter	clinical testing	Published functional studies demonstrates a damaging effect: decrease in protein stability resulting in defective homology directed repair activity (Alenezi et al., 2022); 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, 27616075, 21822267, 35264596, 25938944, 35565380, 32522261, 34923718, 33630411, 33471991, 36315097, 21111057)
Ambry Genetics	RCV000115808	SCV000185614	likely benign	Hereditary cancer-predisposing syndrome	2020-08-13	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	RCV000228533	SCV000287698	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-01-14	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 46 of the RAD51D protein (p.Ser46Cys). This variant is present in population databases (rs587780102, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer, multiple adenomatous polyps, and/or ovarian cancer (PMID: 22986143, 25938944, 27616075, 32522261, 33630411, 35565380). ClinVar contains an entry for this variant (Variation ID: 127882). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects RAD51D function (PMID: 35565380). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000212953	SCV000604997	uncertain significance	not specified	2016-11-02	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115808	SCV000686419	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-07	criteria provided, single submitter	clinical testing	This missense variant replaces serine with cysteine at codon 46 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown the mutant protein to exhibit significantly reduced homology-directed DNA repair function and protein stability (PMID: 35565380). This variant has been observed in at least three individuals affected with ovarian cancer (PMID: 21822267, 22986143, 35565380), in an individual affected with breast cancer (PMID: 27616075), and an individual affected with multiple adenomatous polyps (PMID: 25938944). This variant has not shown a significant association with breast cancer in a large case-control study (3/60463 cases, 1/53460 controls; OR=2.653; 95%CI 0.276 to 25.502; p-value=0.628; Leiden Open Variation Database DB-ID FNDC8_000019) (PMID: 33471991). This variant has been observed in two individuals age 70 years or older without cancer (FLOSSIES; https://whi.color.com/variant/17-33446137-G-C). This variant has been identified in 22/282706 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.
Counsyl	RCV000228533	SCV000784997	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2017-03-15	criteria provided, single submitter	clinical testing
Mendelics	RCV003492493	SCV000839197	likely benign	Hereditary cancer	2024-01-23	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798341	SCV002043210	uncertain significance	Breast and/or ovarian cancer	2020-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000115808	SCV002534771	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-05	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000212953	SCV002760915	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000212953	SCV002819352	uncertain significance	not specified	2023-10-02	criteria provided, single submitter	clinical testing	Variant summary: RAD51D c.137C>G (p.Ser46Cys) results in a non-conservative amino acid change located in the RAD51D, N-terminal domain (IPR048943) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.6e-05 in 251312 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (7.6e-05 vs 0.00013), allowing no conclusion about variant significance. The variant was found in the FLOSSIES database in two European women older than age 70 years who have never had cancer. c.137C>G has been reported in the literature in individuals affected with Breast, Ovarian and Colorectal Cancer (Alenezi_2022, Kraus_2017, Wickramanayake_2012, Loveday_2011, Weren_2015, Velazquez_2020, Guindalini_2022, de Oliveira_2022). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrence with a pathogenic variant has been reported in a Lynch Syndrome case (MSH2 c.2459-1G>C, Ferrer-Avargues_2021). At least one publication reports experimental evidence evaluating an impact on protein function, suggesting impaired homologous recombination functionality (Alenezi_2022). The following publications have been ascertained in the context of this evaluation (PMID: 35565380, 33630411, 35264596, 27616075, 21822267, 32522261, 25938944, 22986143, 35534704). 11 submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified this variant as uncertain significance (n=10) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000228533	SCV004017757	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.
Baylor Genetics	RCV000228533	SCV004208087	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 4	2024-03-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656964	SCV004220162	uncertain significance	not provided	2023-06-06	criteria provided, single submitter	clinical testing	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 35264596 (2022), 35565380 (2022), 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D), 27616075 (2016), 21822267 (2011), 22986143 (2012)), Lynch syndrome (PMID: 33630411 (2021)), and colorectal cancer (PMID: 25938944 (2015)). Additionally, the variant has been reported in healthy individuals (PMIDs: 33471991 (2021) see also LOVD (https://databases.lovd.nl/shared/variants/RAD51D), 22986143 (2012)). One experimental study reports the variant impacts proper RAD51D function, however further studies are needed to determine the global impact of this variant (PMID: 35565380 (2022)). The frequency of this variant in the general population, 0.00013 (17/129118 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354278	SCV001548855	uncertain significance	Malignant tumor of breast		no assertion criteria provided	clinical testing	The RAD51D p.Ser46Cys variant was identified in 1 of 1172 proband chromosomes (frequency: 0.0009) from individuals or families with unselected ovarian cancer or at high risk of breast cancer (and negative for breast and ovarian cancer genes); it was identified in an ovarian cancer case (Wickramanayake 2012). The variant was also identified in dbSNP (ID: rs587780102) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics, Invitae, ARUP Laboratories and Color Genomics Inc), and Clinvitae (3x), but was not identified in Cosmic and LOVD 3.0. The variant was identified in control databases in 25 of 276898 chromosomes at a frequency of 0.00009 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: “Other” in 1 of 6464 chromosomes (freq: 0.0002), Latino in 4 of 34418 chromosomes (freq: 0.0001) and European Non-Finnish in 20 of 126540 chromosomes (freq: 0.0002); but not in the African, Ashkenazi Jewish, East Asian, European Finnish, and South Asian populations. The p.Ser46 residue is conserved in mammals but not in more distantly related organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the Cys 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.
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000656964	SCV002036290	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000656964	SCV002037384	uncertain significance	not provided		no assertion criteria provided	clinical testing