rs376855484
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1PP3_ModerateBS2_Supporting
The NM_002878.4(RAD51D):c.629C>T(p.Ala210Val) variant causes a missense change. The variant allele was found at a frequency of 0.000115 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A210E) has been classified as Uncertain significance.
Frequency
Consequence
NM_002878.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51D | NM_002878.4 | c.629C>T | p.Ala210Val | missense_variant | 7/10 | ENST00000345365.11 | |
RAD51L3-RFFL | NR_037714.1 | n.381C>T | non_coding_transcript_exon_variant | 3/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.629C>T | p.Ala210Val | missense_variant | 7/10 | 1 | NM_002878.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000239 AC: 6AN: 251402Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135870
GnomAD4 exome AF: 0.000124 AC: 181AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.000132 AC XY: 96AN XY: 727240
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74322
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 4 Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 02, 2024 | This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 210 of the RAD51D protein (p.Ala210Val). This variant is present in population databases (rs376855484, gnomAD 0.006%). This missense change has been observed in individual(s) with ovarian cancer, breast cancer, pancreatic cancer, colon cancer and an individual undergoing Lynch syndrome testing (PMID: 24130102, 25452441, 25980754, 26057125, 26261251, 27978560, 28726808). ClinVar contains an entry for this variant (Variation ID: 141969). 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 | Counsyl | Sep 13, 2016 | - - |
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 31, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jan 26, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 08, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with personal and family history of ovarian, breast, or other cancers, and also in unaffected controls from a breast cancer study (Gutierrez-Enriquez et al., 2014; Couch et al., 2015; Janatova et al., 2015; Song et al., 2015; Yurgelun et al., 2015; Pearlman et al., 2017; Chaffee et al., 2018; Velazquez et al., 2020; Dorling et al., 2021; Lerner-Ellis et al., 2021); This variant is associated with the following publications: (PMID: 32322110, 24130102, 26057125, 25452441, 26261251, 25980754, 27978560, 28726808, 32756499, 21111057, 14704354, 33471991, 32885271) - |
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 17, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 17, 2022 | The p.A210V variant (also known as c.629C>T), located in coding exon 7 of the RAD51D gene, results from a C to T substitution at nucleotide position 629. The alanine at codon 210 is replaced by valine, an amino acid with similar properties. This alteration has been reported in individuals affected with breast, ovarian, pancreatic, and colon cancer (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May; Couch FC et al. J. Clin. Oncol. 2015 Feb;33:304-11134:2088-97; Velázquez C et al. Cancers (Basel), 2020 Aug;12; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879; Dorling et al. N Engl J Med. 2021 02;384:428-439; Janatova M et al. PLoS ONE. 2015 Jun;10:e0127711; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Chaffee KG et al. Genet Med, 2018 01;20:119-127; Yurgelun MB et al. Gastroenterology, 2015 Sep;149:604-13.e20). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 22, 2022 | This missense variant replaces alanine with valine at codon 210 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). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in multiple individuals affected with ovarian cancer (PMID: 24130102, 26057125, 26261251), breast cancer (PMID: 25452441), Lynch syndrome associated cancers and/or polyps (PMID: 25980754, 27978560), and pancreatic cancer (PMID: 28726808). It has also been observed in unaffected individuals (PMID: 33471991; Color internal data). This variant has been identified in 8/282794 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2020 | Variant summary: RAD51D c.629C>T (p.Ala210Val) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding 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 2.3e-05 in 257026 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.629C>T has been reported in the literature in individuals affected with Breast/Ovarian Cancer Syndrome, Lynch syndrome, or pancreatic cancer (Gutierrez-Enrquez_2014, Couch_2015, Yurgelun_2015, Janatova_2015, Song_2015, Pearlman_2016, Chaffee_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. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
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.Ala210Val variant was identified in 8 of 16,500 proband chromosomes (frequency: 0.0005) from individuals or families with Lynch syndrome, or pancreatic, breast or ovarian cancer and was not identified in 5538 control chromosomes from healthy individuals (Gutierrez-Enriquez 2013, Couch 2015, Yurgelun 2015, Janatova 2015, Song 2015, Pearlman 2017, Chaffee 2018). The variant was identified in dbSNP (rs376855484) as “with uncertain significance allele” and ClinVar (classified as uncertain significance by Invitae, Color, GeneDx, Ambry Genetics and 2 other submitters). The variant was identified in control databases in 8 of 282,794 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 7 of 129,124 chromosomes (freq: 0.00005) and African in 1 of 24,958 chromosomes (freq: 0.00004), while it was not observed in the Latino, Ashkenazi Jewish, East Asian, Finnish, Other or South Asian populations. The p.Ala210 residue is conserved across mammals and other 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. - |
Hereditary breast ovarian cancer syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Aug 18, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at