ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.620C>T (p.Ser207Leu) (rs370228071)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130934 SCV000185846 likely pathogenic Hereditary cancer-predisposing syndrome 2020-04-27 criteria provided, single submitter clinical testing The p.S207L variant (also known as c.620C>T), located in coding exon 7 of the RAD51D gene, results from a C to T substitution at nucleotide position 620. The serine at codon 207 is replaced by leucine, an amino acid with dissimilar properties. This alteration has previously been reported in individuals with serous peritoneal, breast, and ovarian cancer (Loveday C et al. Nat Genet. 2011 Aug 7;43(9):879-882<span style="color:rgb(0, 0, 0); font-family:arial,helvetica,clean,sans-serif; font-size:11.0045px">; Wickramanayake A et al. Gynecol. Oncol. 2012 Dec;127:552-5; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8; Golmard L et al. BMC Cancer. 2013 Oct;13:484; Shirt BH et al. Genet Med. 2016 Oct;18(10):974-81). In a study by Rivera et al., this alteration showed segregation with disease in two families with ovarian high grade serous carcinoma (HGSC) and in two other families with breast cancer. A case control analysis found strong association with ovarian HGSC (P=2x10<sup>-6</sup>), but no significant association with breast cancer. This same group conducted numerous functional studies and found impaired homologous recombination, XRCC2 binding, and RAD51 foci formation (Rivera B et al. Cancer Res. 2017 Aug;77:4517-4529). This alteration is located in the highly conserved Walker B motif of the RAD51D protein that is required for ATPase function and XRCC2 binding (Rivera B et al. Cancer Res. 2017 Aug;77:4517-4529; Wiese C et al. Nucleic Acids Res. 2006 May;34:2833-43). Structural analysis predicts that this alteration would disrupt important hydrogen bonding and introduce steric clashes that would interfere with protein function (Rivera B et al. Cancer Res. 2017 Aug;77:4517-4529). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000204202 SCV000261711 pathogenic Breast-ovarian cancer, familial 4 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces serine with leucine at codon 207 of the RAD51D protein (p.Ser207Leu). The serine residue is highly conserved and there is a large physicochemical difference between serine and leucine. This variant is present in population databases (rs370228071, ExAC 0.006%). This variant has been observed in individual(s) with ovarian, endometrial cancer, peritoneal carcinoma, and breast cancer (PMID: 22986143, 26976419, 26845104, 21822267, 28646019, 25186627). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142102). This missense change occurs within the conserved RAD51D Walker B domain (amino acid residues 202-207), which has been shown to be necessary for RAD51D to interact with XRCC2 and RAD51C, and for efficient homologous recombinational repair (PMID: 16717288). An experimental study has shown that this missense change disrupts the interaction between RAD51D and XRCC2, causing impaired homologous recombination (PMID: 28646019). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington RCV000130934 SCV000266230 uncertain significance Hereditary cancer-predisposing syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000590382 SCV000292679 likely pathogenic not provided 2021-05-10 criteria provided, single submitter clinical testing Observed in individuals with primary peritoneal, breast, and/or ovarian cancer and co-segregated with ovarian cancer in at least two families (Loveday 2011, Wickramanayake 2012, Golmard 2013, Shirts 2016, Tung 2015, Rivera 2017); Published functional studies suggest a damaging effect: impaired homologous recombination activity (Rivera 2017); Not observed at a significant frequency in large population cohorts (Lek 2016); 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: 16717288, 26845104, 22986143, 21822267, 28646019, 24139550, 26976419, 25186627, 31844177, 31922703)
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000130934 SCV000576437 uncertain significance Hereditary cancer-predisposing syndrome 2017-02-14 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000204202 SCV000611514 uncertain significance Breast-ovarian cancer, familial 4 2017-05-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130934 SCV000686475 likely pathogenic Hereditary cancer-predisposing syndrome 2020-10-15 criteria provided, single submitter clinical testing This missense variant replaces serine with leucine at codon 207 of the RAD51D protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). A functional study reported this variant protein to be abnormal in XRCC2 binding and RAD51 foci formation and partially abnormal in homology-mediated DNA repair (PMID: 28646019). This variant has been observed in multiple individuals affected with breast cancer, ovarian cancer, endometrial cancer and urothelial carcinoma (PMID: 21822267, 22986143, 24139550, 25186627, 28646019, 31844177) and has been reported to segregate with diseases in at least two families (PMID: 28646019). This variant has also been identified in 8/282800 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000722123 SCV000698110 pathogenic Hereditary breast and ovarian cancer syndrome 2020-07-02 criteria provided, single submitter clinical testing Variant summary: RAD51D c.620C>T (p.Ser207Leu) results in a non-conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal and AAA+ ATPase domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 253526 control chromosomes (gnomAD and publication). c.620C>T has been reported in the literature in multiple individuals affected with in multiple individuals affected with Breast, Endometrial, Ovarian cancer and Urothelial carcinoma (example, Loveday_2011, Wickramanayake_2012, Golmard_2013, Rivera_2017, Tung_2016, Tung_2015, Shirts_2016, Nassar_2020). In a conservative assessment of the transmission of this variant as ascertained from the literature, we captured at-least 12 transmissions of the variant allele and 2 transmissions of the reference allele to affected individuals. This variant was reported as being highly prevalent in French Canadians and as being associated with a high risk for ovarian high-grade serous carcinoma (HGSC) (3.8% cases vs. 0.2% controls), but was not associated with risk for breast, endometrial, pancreas or colorectal cancers (Rivera_2017). The authors conclude this variant as a bona fide pathogenic RAD51D missense cancer susceptibility allele and is one of the most frequently observed alleles conferring high risk of ovarian high-grade serous carcinoma (HGSC) in the French Canadian population of Quebec. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Rivera_2017). The most pronounced variant effect results in a disruption the RAD51D-XRCC2 interaction, impaired homologous recombination and sensitivity to PARP-inhibitor therapies. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (pathogenic, n=1; likely pathogenic, n=5; VUS, n=3). Some submitters cite overlapping evidence utilized in the context of this evaluation and have re-classified this variant to the pathogenic spectrum since its previous evaluation. Based on the evidence outlined above, the variant was classified as pathogenic.
Counsyl RCV000204202 SCV000786574 likely pathogenic Breast-ovarian cancer, familial 4 2018-05-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590382 SCV001134805 likely pathogenic not provided 2019-02-22 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001270344 SCV001450568 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing __The RAD51D p.Ser207Leu variant was identified in 13 of 682 proband chromosomes (frequency: 0.0190615835777126) from individuals or families with __and was present in 2 of 1860 control chromosomes (frequency: 0.0010752688172043) from healthy individuals (Rivera_2017_PMID: 28646019). The variant was identified in dbSNP (ID: rs370228071) as conflicting interpretations of pathogenicity and likely pathogenic, ClinVar (Conflicting interpretations of pathogenicity. Likely pathogenic by: Counsyl in 2018, Ambry in 2018, Integrated Genetics in 2018, GeneDx in 2018, Quest Diagnostics in 2019, Color in 2018, Invitae in 2019. VUS by: Institute for biomarker research in 2017, University of Washington in 2015, Fulgent in 2017), and LOVD 3.0 (one entry, not classified, effect unknown) databases. The variant was not identified in the Cosmic database. The variant was identified in control databases in 8 of 282800 chromosomes at a frequency of 0.00002829 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Other in 1 of 7224 chromosomes (freq: 0.000138), East Asian in 1 of 19954 chromosomes (freq: 0.00005), European (non-Finnish) in 6 of 129132 chromosomes (freq: 0.000046), but was not observed in the African, Latino, Ashkenazi Jewish, European (Finnish), or South Asian populations. The p.Ser207 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 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) do not predict a difference in splicing. This variant is located in the RAD51C binding domain and the Walker B motif, which is important in homologous repair (Wiese_2006_16717288). The c.620C>T variant was shown to disrupt the interaction between RAD51D and XRCC2, which cause impaired homologous recombination (Rivera_2017_PMID: 28646019). __Rivera et al. (2017) identified this variant in 3.81% of high grade serous ovarian cancer cases and 0.2% of unaffected controls in the French Canadian population (Rivera_2017_PMID: 28646019). __The variant segregated with ovarian high-grade serous carcinoma in 3 families (Rivera_2017_PMID: 28646019). 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 pathogenic role for this variant. This variant is classified as likely pathogenic.

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