17-58696794-T-C
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1BP4_ModerateBP6
The NM_058216.3(RAD51C):c.506T>C(p.Val169Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,613,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict 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. V169M) has been classified as Uncertain significance.
Frequency
Consequence
NM_058216.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.506T>C | p.Val169Ala | missense_variant | 3/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.506T>C | p.Val169Ala | missense_variant | 3/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152060Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000163 AC: 41AN: 251466Hom.: 0 AF XY: 0.000110 AC XY: 15AN XY: 135906
GnomAD4 exome AF: 0.000209 AC: 306AN: 1461868Hom.: 0 Cov.: 32 AF XY: 0.000179 AC XY: 130AN XY: 727232
GnomAD4 genome AF: 0.0000855 AC: 13AN: 152060Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74258
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 28, 2021 | This variant is associated with the following publications: (PMID: 26689913, 18203022, 28829762, 21537932, 20400964, 25470109, 22370629, 22476429, 25980754, 21990120, 25801821, 27443514, 23117857, 26261251, 22538716) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 22, 2023 | In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMID: 22538716 (2012), 21990120 (2012), 22370629 (2012), 22476429 (2012), and 20400964 (2010)). The variant has also been identified in individuals affected with either a history of Lynch syndrome-associated cancer and/or polyps, B-cell chronic lymphocytic leukemia, endometrial carcinoma, or low grade glioma (PMID: 27443514 (2016), 26689913 (2015), 25980754 (2015), 18203022 (2008)). In a large-scale breast cancer association study, the variant was observed in individuals with breast cancer as well as unaffected individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). Assessment of experimental studies yielded non-damaging results regarding the impact of this variant on protein function (PMID: 20400964 (2010)). The frequency of this variant in the general population, 0.00033 (42/129164 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 conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 11, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 01, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 06, 2023 | This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752]. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | May 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 08, 2018 | 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Nov 19, 2014 | - - |
Fanconi anemia complementation group O Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jul 11, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 169 of the RAD51C protein (p.Val169Ala). This variant is present in population databases (rs587780256, gnomAD 0.03%). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 18203022, 20400964, 21990120, 22370629, 22476429, 22538716, 25980754, 26689913, 27443514, 34326862). This variant is also known as 4150T>C. ClinVar contains an entry for this variant (Variation ID: 128206). 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 does not substantially affect RAD51C function (PMID: 20400964). 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 | Nov 14, 2022 | - - |
Malignant tumor of breast Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RAD51C p.Val169Ala variant was identified in 11 of 30,036 proband chromosomes (frequency: 0.0004) from individuals or families with chronic lymphocytic leukemia, Lynch Syndrome, glioma, endometrial, and hereditary breast and ovarian cancer and was present in 2 of 16,372 control chromosomes (frequency: 0.0001) from healthy individuals (Sellick 2008, Meindl 2009, Lu 2012, De Leeneer 2012, Thompson 2012, Loveday 2012, Yurgelun 2015, Ring 2016, Lu 2015, Song 2015). The variant was identified in dbSNP (rs587780256) as “with uncertain significance allele”, in ClinVar (classified as likely benign by Ambry Genetics, Color and GeneDx, uncertain significance by Invitae and Counsyl and benign by Integrated Genetics) and LOVD 3.0 (observed 4x). The variant was identified in control databases in 42 of 282,840 chromosomes at a frequency of 0.0001 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 42 of 129,164 chromosomes (freq: 0.0003); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, Finnish, Other and South Asian populations. In one study in vitro expressio n of the variant had a similar effect on cell survival and RAD51C protein expression compared to wild type (Meindl 2009). The p.Val169 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 1 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Feb 14, 2024 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at