chr17-35107113-A-G
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_002878.4(RAD51D):c.355T>C(p.Cys119Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,972 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 0.000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.00014 ( 1 hom. )
Consequence
RAD51D
NM_002878.4 missense
NM_002878.4 missense
Scores
3
15
Clinical Significance
Conservation
PhyloP100: 1.02
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 -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.17148542).
BP6
Variant 17-35107113-A-G is Benign according to our data. Variant chr17-35107113-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 182856.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=9}.
BS2
High AC in GnomAd4 at 10 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RAD51D | NM_002878.4 | c.355T>C | p.Cys119Arg | missense_variant | 5/10 | ENST00000345365.11 | NP_002869.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RAD51D | ENST00000345365.11 | c.355T>C | p.Cys119Arg | missense_variant | 5/10 | 1 | NM_002878.4 | ENSP00000338790.6 | ||
| ENSG00000267618 | ENST00000593039.5 | c.4-632T>C | intron_variant | 2 | ENSP00000466834.1 |
Frequencies
GnomAD3 genomes 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000517 AC: 13AN: 251406Hom.: 0 AF XY: 0.0000589 AC XY: 8AN XY: 135870
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GnomAD4 exome AF: 0.000143 AC: 209AN: 1461826Hom.: 1 Cov.: 32 AF XY: 0.000135 AC XY: 98AN XY: 727212
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GnomAD4 genome 0.0000657 AC: 10AN: 152146Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74336
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 17, 2015 | - - |
| Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | May 03, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 27, 2023 | The p.C119R variant (also known as c.355T>C), located in coding exon 5 of the RAD51D gene, results from a T to C substitution at nucleotide position 355. The cysteine at codon 119 is replaced by arginine, an amino acid with highly dissimilar properties. This alteration has been reported in multiple breast and/or ovarian cancer cohorts (Osher DJ et al. Br. J. Cancer, 2012 Apr;106:1460-3; Gutiérrez-Enríquez S et al. Int J Cancer, 2014 May;134:2088-97; Tung N et al. Cancer, 2015 Jan;121:25-33; Song H et al. J Clin Oncol, 2015 Sep;33:2901-7; Penkert J et al. Breast Cancer Res, 2018 08;20:87). Additionally, this variant was reported in 8/60,466 breast cancer cases and in 9/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 16, 2021 | Variant summary: RAD51D c.355T>C (p.Cys119Arg) results in a non-conservative amino acid change located in the AAA+ ATPase domain of 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 5.8e-05 in 256850 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in RAD51D causing Hereditary Breast And Ovarian Cancer Syndrome (5.8e-05 vs 0.00013), allowing no conclusion about variant significance. c.355T>C has been reported in the literature in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome in the absence of BRCA mutations, as well as pancreatic cancer and prostate cancer (Osher_2012, Gutierrez-Enriques_2014, Song_2015, Tung_2015, Shindo_2017, Lu_2015, Penkert_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation; five classified as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 11, 2022 | In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal or family history including breast, ovarian, pancreatic, and other cancers (Osher et al., 2012; Song et al., 2015; Shindo et al., 2017; Penkert et al., 2018); This variant is associated with the following publications: (PMID: 28767289, 22415235, 24130102, 26261251, 28492532, 30086788, 14704354, 19327148, 21111057, 34923718, 27535533) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 27, 2024 | The RAD51D c.355T>C (p.Cys119Arg) variant has been reported in the published literature in individuals affected with prostate cancer (PMID: 26689913 (2015)), breast and/or ovarian cancer as well as in reportedly healthy individuals (PMIDs: 33471991 (2021), 30086788 (2018), 26261251 (2015), 25186627 (2015), 24130102 (2014), 22415235 (2012), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51D)). The frequency of this variant in the general population, 0.000085 (11/129168 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 predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 12, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 119 of the RAD51D protein (p.Cys119Arg). This variant is present in population databases (rs201313861, gnomAD 0.009%). This missense change has been observed in individual(s) with breast cancer, ovarian cancer, and/or pancreatic ductal adenocarcinoma (PMID: 22415235, 24130102, 25186627, 26261251, 28767289, 30086788). This variant is also known as c.415A>G (p.C139R). ClinVar contains an entry for this variant (Variation ID: 182856). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD51D protein function with a negative predictive value of 80%. 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. - |
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 | Apr 20, 2021 | - - |
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.Cys119Arg variant was identified in 4 of 8892 proband chromosomes (frequency: 0.0004) from individuals or families with breast and ovarian cancer and was present in 2 of 5544 control chromosomes (frequency: 0.0004) from healthy individuals (Gutierrez-Enriquez 2013, Osher 2012, Song 2015). The variant was also identified in dbSNP (ID: rs201313861) as “With Uncertain significance allele”, and in ClinVar (classified as uncertain significance by GeneDx, Ambry genetics, Invitae, LCOA clinical laboratory). The variant was not identified in the Cosmic database. The variant was identified in control databases in 15 of 277134 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). It was observed in the following populations: African in 1 of 24020 chromosomes (freq: 0.00004), Latino in 3 of 34420 chromosomes (freq: 0.0001), European in 11 of 126692 chromosomes (freq: 0.0001); it was not observed in the “Other”, Ashkenazi Jewish, East Asian, Finnish, and South Asian populations. The p.Cys119 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 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. 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. - |
Hereditary breast ovarian cancer syndrome Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Apr 09, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T;T;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
.;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;.
PROVEAN
Benign
N;.;.;.
REVEL
Benign
Sift
Benign
T;.;.;.
Sift4G
Benign
T;T;T;.
Polyphen
P;P;.;.
Vest4
MVP
MPC
0.15
ClinPred
T
GERP RS
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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