17-35119588-C-G
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Variant summary
Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2
The NM_002878.4(RAD51D):c.26G>C(p.Cys9Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,612,440 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00068 ( 1 hom. )
Consequence
RAD51D
NM_002878.4 missense
NM_002878.4 missense
Scores
2
11
5
Clinical Significance
Conservation
PhyloP100: 3.45
Genes affected
RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -11 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.23021111).
BP6
Variant 17-35119588-C-G is Benign according to our data. Variant chr17-35119588-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127886.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=11, Likely_benign=7}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.000675 (986/1460118) while in subpopulation NFE AF= 0.000831 (924/1111920). AF 95% confidence interval is 0.000787. There are 1 homozygotes in gnomad4_exome. There are 499 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 72 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.000473 AC: 72AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000372 AC: 92AN: 247570Hom.: 1 AF XY: 0.000410 AC XY: 55AN XY: 134222
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GnomAD4 exome AF: 0.000675 AC: 986AN: 1460118Hom.: 1 Cov.: 31 AF XY: 0.000687 AC XY: 499AN XY: 726452
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GnomAD4 genome 0.000473 AC: 72AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.000336 AC XY: 25AN XY: 74484
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:12Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:4Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 06, 2023 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Division of Medical Genetics, University of Washington | Dec 16, 2019 | This variant has been reported in the literature in individuals with breast and/or ovarian cancer (Wickramanayake 2012, Gutierrez-EnrÃquez 2014, Song 2015). This variant has an allele frequency of 0.0004 in the Broad Institute gnomAD Browser (https://gnomad.broadinstitute.org/). In silico analyses indicate this is an evolutionarily conserved residue. Thus, it is unknown at this time whether this variant increases cancer risk. PP3 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 21, 2022 | The RAD51D c.26G>C; p.Cys9Ser variant (rs140825795; ClinVar Variation ID: 127886), has been previously reported in several ovarian cancer cohort (selected references: Wickramanayake 2012 and Song 2015), but in many cases has was also identified in control populations (Weitzel 2019). This variant is found in the general population with an overall allele frequency of 0.04% (113/278,930 alleles) in the Genome Aggregation Database. The cysteine at codon 9 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.218). Based on the available information, the clinical significance of this variant is uncertain References: Song et al. Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population. J Clin Oncol. 2015 Sep 10;33(26):2901-7. PMID: 26261251 Weitzel et al. Pathogenic and likely pathogenic variants in PALB2, CHEK2, and other known breast cancer susceptibility genes among 1054 BRCA-negative Hispanics with breast cancer. Cancer. 2019 Aug 15;125(16):2829-2836. PMID: 31206626 Wickramanayake et al. Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Gynecol Oncol. 2012 Dec;127(3):552-5. PMID: 22986143 - |
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
not provided Uncertain:3Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | RAD51D: BP4, BS2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 29, 2018 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 18, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2024 | Observed in individuals with a personal and/or family history of breast, ovarian, and/or colorectal cancer, as well as in controls (PMID: 21822267, 22986143, 24139550, 24130102, 26261251, 25186627, 28135145, 29522266, 31206626, 33471991, 36315097, 35264596, 34326862, 33606809, 32885271); 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, 28135145, 21822267, 24130102, 26261251, 24139550, 25340522, 27498913, 25186627, 29522266, 31007844, 34117267, 33471991, 36315097, 31206626, 34923718, 35264596, 21111057, 35980532, 33606809, 33203166, 29641532, 30306255, 34326862, 32885271, 36977404) - |
not specified Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 26, 2024 | Variant summary: RAD51D c.26G>C (p.Cys9Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00037 in 258298 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 3 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 benign. c.26G>C, has been reported in the literature in individuals affected with Breast and Ovarian Cancer or other cancers and also in controls (example, Wickramanyake_2012, Gutirrez-Enrquez_2013, Loveday_2011, Golmard_2013, Song_2015, Yurgelun_2017, Tung_2015, Madeddu_2019, Weitzel_2019). In addition, this variant has been reported in 10/9884 individuals who are at least 70 years old and cancer-free in the FLOSSIES database. At-least two co-occurrences with other pathogenic variant(s) have been observed at our laboratory (BRCA1 c.5266dup, p.Gln1756fs) and reported in the literature (BRCA2 c.5851_5854del, p.Ser1951Trpfs*11, Tung_2015), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25340522, 24139550, 24130102, 21822267, 31007844, 26261251, 25186627, 31206626, 22986143, 28135145). ClinVar contains an entry for this variant (Variation ID: 127886). Based on the evidence outlined above, the variant was classified as likely benign. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Oct 12, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Feb 06, 2024 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 26, 2021 | 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. - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 07, 2020 | This missense variant replaces cysteine with serine at codon 9 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been observed in individuals affected with breast and/or ovarian cancer (PMID: 21822267, 22986143, 24130102, 24139550, 26261251), cervical cancer (PMID: 31007844) and healthy controls and unaffected individuals (PMID: 21822267, 26261251; FLOSSIES database at https://whi.color.com/variant/17-33446607-C-G). This variant has been identified in 113/278930 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. - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Sep 09, 2021 | - - |
Breast and/or ovarian cancer Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 08, 2023 | - - |
Malignant tumor of breast Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RAD51D p.Cys9Ser variant was identified in 9 of 12002 proband chromosomes (frequency: 0.0007) from Spanish, British and American individuals or families with BRCA1/2 negative breast/ovarian cancer or ovarian cancer and was identified in 3 of 7674 chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Loveday 2011, Wickramanayake 2012, Song 2015). A case-control study of 3,429 patients with invasive ovarian cancer (unselected for family history) and 2,772 controls sequenced for RAD51B/C/D mutations found that RAD51C and RAD51D are moderate ovarian cancer susceptibility genes (Song 2015). The variant was identified in dbSNP (ID: rs140825795) “With Uncertain significance allele”, ClinVar (classified uncertain significance by GeneDx, Ambry Genetics, Invitae, Counsyl, Color Genomics Inc. and Quest Diagnostics Nichols Institute San Juan Capistrano), Clinvitae (3x), and was not identified in Cosmic or LOVD 3.0. The variant was also identified in control databases in 109 (1 homozygous) of 273460 chromosomes at a frequency of 0.0004 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 4 of 23938 chromosomes (freq: 0.0002), “Other” in 2 of 6436 chromosomes (freq: 0.0003), Latino in 13 (1 homozygous) of 34392 chromosomes (freq: 0.0004), European Non-Finnish in 88 of 124366 chromosomes (freq: 0.0007), European Finnish in 2 of 24602 chromosomes (freq: 0.00008); it was not observed in the Ashkenazi Jewish, East Asian, and South Asian populations. The p.Cys9Ser residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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. - |
RAD51D-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 04, 2024 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D
M_CAP
Uncertain
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;M;M
PROVEAN
Pathogenic
D;D;D;.
REVEL
Benign
Sift
Uncertain
D;D;D;.
Sift4G
Uncertain
D;D;T;D
Polyphen
P;P;D;.
Vest4
MutPred
Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);Gain of disorder (P = 0.0024);
MVP
MPC
0.37
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at