17-35103277-G-A
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2
The NM_002878.4(RAD51D):c.715C>T(p.Arg239Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000199 in 1,611,014 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R239G) has been classified as Uncertain significance.
Frequency
Consequence
NM_002878.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51D | NM_002878.4 | c.715C>T | p.Arg239Trp | missense_variant | 8/10 | ENST00000345365.11 | |
RAD51L3-RFFL | NR_037714.1 | n.467C>T | non_coding_transcript_exon_variant | 4/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.715C>T | p.Arg239Trp | missense_variant | 8/10 | 1 | NM_002878.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000285 AC: 7AN: 245232Hom.: 0 AF XY: 0.0000227 AC XY: 3AN XY: 132412
GnomAD4 exome AF: 0.0000192 AC: 28AN: 1458878Hom.: 1 Cov.: 32 AF XY: 0.0000165 AC XY: 12AN XY: 725390
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152136Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74322
ClinVar
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 07, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 16, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with ovarian cancer, some of whom are reported to also carry the pathogenic variant RAD51D Arg232Ter (Wickramanayake et al., 2012; Gutierrez-Enrquez et al., 2014; Song et al., 2015; Sanchez-Bermudez et al., 2018); This variant is associated with the following publications: (PMID: 24130102, 22986143, 26261251, 29409816, 35366121, 19327148, 21111057, 14704354) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RAD51D p.Arg239Trp variant was identified in 8 of 10584 proband chromosomes (frequency: 0.0008) from individuals or families with breast or ovarian cancer and was not identified in 5624 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Sanchez-Bermudez 2018, Song 2015, Wickramanayake 2012). The variant was also identified in several population studies with a co-occurring pathogenic RAD51D variant (c.694C>T, p.Arg232*) in multiple members of same families (Sanchez-Bermudez 2018, Gutierrez-Enriquez 2013, Wickramanayake 2012). The variant was also identified in dbSNP (ID: rs770250516) as "With Uncertain significance allele", and in ClinVar (classified as uncertain significance by Invitae, Ambry Genetics and four other submitters). The variant was identified in control databases in 9 of 271100 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 1 of 6340 chromosomes (freq: 0.0002), European in 5 of 123902 chromosomes (freq: 0.00004), East Asian in 2 of 18598 chromosomes (freq: 0.0001), and South Asian in 1 of 29868 chromosomes (freq: 0.00003), while the variant was not observed in the African, Latino, Ashkenazi Jewish, or Finnish populations. The p.Arg239 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. 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. - |
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Aug 02, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 27, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 239 of the RAD51D protein (p.Arg239Trp). This variant is present in population databases (rs770250516, gnomAD 0.01%). This missense change has been observed in individual(s) with ovarian cancer (PMID: 22986143, 24130102, 26261251, 29409816). ClinVar contains an entry for this variant (Variation ID: 187225). 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. - |
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 | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 16, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 13, 2015 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 23, 2022 | The p.R239W variant (also known as c.715C>T), located in coding exon 8 of the RAD51D gene, results from a C to T substitution at nucleotide position 715. The arginine at codon 239 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is reported to co-occur with the p.R232* (c.694C>T) pathogenic RAD51D mutation in a proband with ovarian cancer at age 43 (Wickramanyake A et al. Gynecol. Oncol. 2012 Dec;127:552-5). In another family, both alterations were found in a proband with ovarian cancer at age 44 and in four of her healthy siblings (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May;134:2088-97). Both of these alteration are also reported in a third family with two sisters with ovarian cancer at ages 47 and 46 and their three unaffected children (Sanchez-Bermudez AI et al. Eur J Med Genet. 2018 Jun;61(6):355-361). This variant was reported in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). 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. - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at