rs587780255
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP3_Moderate
The NM_058216.3(RAD51C):βc.428A>Gβ(p.Gln143Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,614,102 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 (β β ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q143E) has been classified as Uncertain significance.
Frequency
Consequence
NM_058216.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.428A>G | p.Gln143Arg | missense_variant | 3/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.428A>G | p.Gln143Arg | missense_variant | 3/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152234Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000358 AC: 9AN: 251480Hom.: 0 AF XY: 0.0000441 AC XY: 6AN XY: 135912
GnomAD4 exome AF: 0.000108 AC: 158AN: 1461868Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80AN XY: 727232
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152234Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:3
Likely pathogenic, flagged submission | curation | Leiden Open Variation Database | Nov 02, 2014 | Curator: Arleen D. Auerbach. Submitter to LOVD: Christine Rappaport. - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 13, 2023 | 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: 25086635, 26740214, 27622768, 28829762, 28873162, 24993905, 24800917, 25154786, 25470109, 22538716, 26261251, 25292178, 21537932, 22451500, 26720728, 26976419, 23117857, 29409816, 29522266, 29641532, 32008151, 14704354, 36099300, 33359728, 35039523) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 08, 2022 | In the published literature, this variant has been reported in in individuals/families with breast and/or ovarian cancer as well as in unaffected controls (PMIDs: 21537932 (2011), 22538716 (2012), 24993905 (2014), 26261251 (2015), 26720728 (2016), 26976419 (2016), 26740214 (2016), 27622768 (2017), 33471991 (2021), 35039523 (2022), see also LOVD (http://databases.lovd.nl/shared/genes/ RAD51C). Functional studies were inconclusive regarding the effect of this variant on RAD51C protein function (PMIDs: 22451500 (2012), 25292178 (2015), 36099300 (2022), 35039523 (2022), and 37253112 (2023)). The frequency of this variant in the general population, 0.000079 (9/113756 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Dec 20, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 23, 2023 | This missense variant replaces glutamine with arginine at codon 143 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional studies have shown that this variant partially impairs RAD51 foci formation, homologous recombination and cell cycle control (PMID: 22451500, 25292178) and results in reduced RAD51C binding to RAD51B, RAD51D and XRCC3 (PMID: 36099300). This variant has been reported in three individuals affected with ovarian cancer (PMID: 26261251, 26720728, 35039523) and over ten individuals with breast cancer (PMID: 21537932, 22451500, 22538716, 24993905, 26740214, 26976419, 27622768, 35039523). In a familial breast cancer case-control study, this variant has been identified in 4/5,734 cases and 3/14,382 controls (PMID: 35039523). This variant has been identified in 9/251480 chromosomes in the general population by the Genome Aggregation Database (gnomAD) and in dozens of individuals lacking a personal history of ovarian or breast cancer (Color internal data). 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 | clinical testing | Ambry Genetics | Nov 29, 2023 | The p.Q143R variant (also known as c.428A>G), located in coding exon 3 of the RAD51C gene, results from an A to G substitution at nucleotide position 428. The glutamine at codon 143 is replaced by arginine, an amino acid with highly similar properties. This alteration has been detected in 2/6237 ovarian cancer patients and 1/5084 healthy control individuals across multiple studies (Loveday C et al. Nat. Genet. 2012 May;44:475-6; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). In another study, this alteration was reported in 0.07% (4/ 5,734) hereditary breast and ovarian cancer families and 0.02% (3/4,382) cancer-free female controls (Lim BWX et al. NPJ Breast Cancer, 2022 Jan;8:10). Further, this variant has been detected in multiple breast cancer patients (Romero A et al. Breast Cancer Res. Treat. 2011 Oct;129:939-46; Jønson L et al. Breast Cancer Res. Treat. 2016 Jan;155:215-22; Tung N et al. J. Clin. Oncol. 2016 May;34:1460-8). One functional study revealed that RAD51C-deficient cells transfected with this variant were unable to restore RAD51C foci-formation to levels comparable to wild type (less than 50% of wild type foci-formation) (Osorio A et al. Hum. Mol. Genet. 2012 Jul;21:2889-98). 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. - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 27, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Dr. med. U. Finckh, Human Genetics, Eurofins MVZ | Sep 01, 2023 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Nov 06, 2020 | DNA sequence analysis of the RAD51C gene demonstrated a sequence change, c.428A>G, in exon 3 that results in an amino acid change, p.Gln143Arg. This sequence change has been described in the gnomAD database with a frequency of 0.008% in the European sub-population (dbSNP rs587780255). The p.Gln143Arg change has been reported in individuals with breast or ovarian cancer and a breast cancer family, however co-segregation studies were not performed (PMID: 22451500, 22538716, 21537932, 26976419, 26720728, 26740214). The p.Gln143Arg change affects a highly conserved amino acid residue located in a domain of the RAD51C protein that is known to be functional. The p.Gln143Arg substitution appears to be deleterious using several in-silico pathogenicity prediction tools (SIFT, PolyPhen2, Align GVGD, REVEL). Functional studies demonstrated reduced protein activity, reduced homologous recombination activity, increased sensitivity to PARP inhibitors, and failure to suppress cell cycle accumulation compared to the wild-type protein (PMIDs: 22451500, 25292178). Due to insufficient evidence, the clinical significance of the p.Gln143Arg change remains unknown at this time. - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2018 | - - |
RAD51C-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 09, 2023 | The RAD51C c.428A>G variant is predicted to result in the amino acid substitution p.Gln143Arg. This variant has been reported in individuals with a history of breast and ovarian cancer (Osorio et al. 2012. PubMed ID: 22451500; Supplementary Table 3, Loveday et al. 2012. PubMed ID: 22538716; Figure S4, Romero et al. 2011. PubMed ID: 21537932; Table A2, Tung et al. 2016. PubMed ID: 26976419; Table 1, Gevensleben et al. 2014. PubMed ID: 24993905; Table A3, Song et al. 2015. PubMed ID: 26261251; Norquist et al. 2016. PubMed ID: 26720728; Neidhardt et al. 2017. PubMed ID: 27622768). In at least one family study, this variant segregated with breast cancer in an individual who inherited the variant from her affected mother. However, in the same family an unaffected maternal aunt was positive for the same variant (Figure 1B, JΓΈnson et al. 2016. PubMed ID: 26740214). It has been reported in cases and controls from a breast cancer cohort study (Table S1, Lim et al. 2022. PubMed ID: 35039523). Functional studies of the RAD51C protein suggest this variant impacts protein activity (Osorio et al. 2012. PubMed ID: 22451500), specifically homologous recombination, sensitivity to polymerase inhibitors, and cell cycle function (Somyajit et al. 2015. PubMed ID: 25292178). This variant is reported in 0.0079% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-56774077-A-G) and is interpreted as uncertain significance by the vast majority of ClinVar submitters (https://www.ncbi.nlm.nih.gov/clinvar/variation/128205/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 143 of the RAD51C protein (p.Gln143Arg). This variant is present in population databases (rs587780255, gnomAD 0.008%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 21537932, 22451500, 22538716, 26720728, 26740214, 26976419). ClinVar contains an entry for this variant (Variation ID: 128205). 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 RAD51C protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects RAD51C function (PMID: 22451500, 25292178). 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at