chr17-35101008-A-T
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The ENST00000345365.11(RAD51D):c.932T>A(p.Ile311Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000185 in 1,613,870 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. I311V) has been classified as Uncertain significance.
Frequency
Genomes: 𝑓 0.00023 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 2 hom. )
Consequence
RAD51D
ENST00000345365.11 missense
ENST00000345365.11 missense
Scores
9
9
Clinical Significance
Conservation
PhyloP100: 3.69
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 -13 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.0075879693).
BP6
Variant 17-35101008-A-T is Benign according to our data. Variant chr17-35101008-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127896.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=8, Likely_benign=7}.
BS1
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00023 (35/152296) while in subpopulation EAS AF= 0.00425 (22/5180). AF 95% confidence interval is 0.00287. There are 1 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 35 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| RAD51D | NM_002878.4 | c.932T>A | p.Ile311Asn | missense_variant | 10/10 | ENST00000345365.11 | NP_002869.3 | |
| RAD51L3-RFFL | NR_037714.1 | n.655+193T>A | intron_variant, non_coding_transcript_variant |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| RAD51D | ENST00000345365.11 | c.932T>A | p.Ile311Asn | missense_variant | 10/10 | 1 | NM_002878.4 | ENSP00000338790 | P1 |
Frequencies
GnomAD3 genomes 0.000230 AC: 35AN: 152178Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000445 AC: 112AN: 251488Hom.: 1 AF XY: 0.000419 AC XY: 57AN XY: 135922
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GnomAD4 exome AF: 0.000181 AC: 264AN: 1461574Hom.: 2 Cov.: 30 AF XY: 0.000193 AC XY: 140AN XY: 727114
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GnomAD4 genome 0.000230 AC: 35AN: 152296Hom.: 1 Cov.: 32 AF XY: 0.000322 AC XY: 24AN XY: 74468
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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
not provided Uncertain:4Benign:2
| Uncertain significance, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 22, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 03, 2021 | 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, 26824983, 32019284, 18951446, 28961279, 29263802, 29522266, 29338689, 30111881, 31159747, 31514334, 32255556, 32566746, 33785725, 32068069) - |
| Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Aug 01, 2024 | RAD51D: BP4, BS1 - |
| Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 17, 2024 | BS1 - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:3
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 11, 2019 | - - |
| Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Jul 14, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 23, 2020 | 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. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneKor MSA | Aug 01, 2018 | - - |
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:2Benign:1
| 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 | Counsyl | Oct 11, 2016 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 01, 2024 | - - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | May 11, 2020 | DNA sequence analysis of the RAD51D gene demonstrated a sequence change, c.932T>A, in exon 10 that results in an amino acid change, p.Ile311Asn. This sequence change has been described in the gnomAD database with a frequency of 0.43% in the East Asian sub-population (dbSNP rs145309168). The p.Ile311Asn change has been reported in individuals with ovarian, breast, and peritoneal cancers (PMIDs: 30111881, 26824983, 22986143). Additionally, two different amino acid changes at the same location, p.Ile311Val and p.Ile311Met, have been reported for predisposition to hereditary breast and ovarian cancer (PMID: 31159747). The p.Ile311Asn change affects a highly conserved amino acid residue located in a domain of the RAD51D protein that is not known to be functional. The p.Ile311Asn substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Due to these contrasting evidences and the lack of functional studies, the clinical significance of the p.Ile311Asn change remains unknown at this time. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
RAD51D-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2024 | The RAD51D c.932T>A variant is predicted to result in the amino acid substitution p.Ile311Asn. This variant has been reported in over 25 individuals with a personal or family history of breast and/or ovarian cancer (Lin et al. 2016. PubMed ID: 26824983; Table 2 Wong et al. 2016. PubMed ID: 29263802; Supp. Table 1 in Kwong et al. 2020. PubMed ID: 32068069; Hauke et al. 2018. PubMed ID: 29522266; Gervas et al. 2021. PubMed ID: 33785725; Table S5. Tsaousis et al. 2019. PubMed ID: 31159747). This variant has also been reported in individuals with a personal or family history of ovarian cancer (Table 2, Wickramanayake et al. 2012. PubMed ID: 22986143; Konstanta et al. 2018. PubMed ID: 301118810), an individual with gastric cancer (Tedaldi et al. 2019. PubMed ID: 31514334), and an individual with pancreatic ductal adenocarcinoma (Supp. Table 2 Cremin et al. 2020. PubMed ID: 32255556). This variant is reported in 0.43% of alleles in individuals of East Asian descent in gnomAD, including 1 homozygote. The c.932T>A variant has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/127896/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
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.Ile311Asn variant was identified in 6 of 1426 proband chromosomes (frequency: 0.0042) from individuals or families with breast and ovarian cancer (Lin 2016, Wickramanayake 2012, Wong 2016). The variant was also identified in dbSNP (ID: rs145309168) as “With Uncertain significance, other allele”, ClinVar (as likely benign by Invitae and as uncertain significance by GeneDx, Ambry Genetics and Counsyl), and Clinvitae databases. The variant was not identified in the Cosmic database. The variant was identified in control databases in 122 of 277230 chromosomes at a frequency of 0.00044 in the following populations: European (Non-Finnish) in 26 of 126716 chromosomes (freq. 0.0002), East Asian in 83 (1 homozygous) of 18868 chromosomes (freq. 0.004), European (Finnish) in 2 of 25794 chromosomes (freq. 0.00008) and South Asian in 9 of 30782 chromosomes (freq. 0.0003), and Other in 2 of 6468 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant is located in the ATPase domain of the RAD51D protein (Kim 2011). The p.Ile311Asn residue is conserved in mammals but not in more distantly related organisms, and 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, 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Cancer Genomics Group, Japanese Foundation For Cancer Research | May 01, 2019 | - - |
Breast and/or ovarian cancer Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Jun 11, 2021 | - - |
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
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Uncertain
D;D;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PROVEAN
Uncertain
D;.;.;.;.
REVEL
Uncertain
Sift
Uncertain
D;.;.;.;.
Sift4G
Benign
T;T;D;T;D
Polyphen
D;D;D;.;.
Vest4
MVP
MPC
0.40
ClinPred
T
GERP RS
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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