17-58696780-T-G
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PP3_Moderate
The NM_058216.3(RAD51C):āc.492T>Gā(p.Phe164Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 1,614,210 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_058216.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152218Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251476Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135908
GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727236
GnomAD4 genome AF: 0.0000656 AC: 10AN: 152336Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74494
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:4
The p.F164L variant (also known as c.492T>G), located in coding exon 3 of the RAD51C gene, results from a T to G substitution at nucleotide position 492. The phenylalanine at codon 164 is replaced by leucine, an amino acid with highly similar properties. This variant was identified in a cohort of 85 patients undergoing HBOC testing in Colombia (Cock-Rada AM et al. Fam. Cancer, 2018 01;17:23-30). This variant was also identified in an individual diagnosed with breast cancer (Weitzel JN et al. Cancer, 2019 08;125:2829-2836). This variant was reported in 2/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med 2021 02;384:428-439). This amino acid position is highly 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. -
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This missense variant replaces phenylalanine with leucine at codon 164 of the RAD51C protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast and/or ovarian cancer, and one of them carried a pathogenic BRCA1 variant (PMID: 28528518; Vazquez-Juarez et al, poster P3-07-07, SABCS 2021). In an international breast cancer case-control meta-analysis, this variant was detected in 2/60466 cases and 3/53461 unaffected controls (PMID: 33471991). This variant has been identified in 10/251476 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. -
c.492T>G, located in exon 3 of the RAD51C gene, is predicted to result in the substitution of phenilalanine by leucine at codon 164, p.(Phe164Leu). This variant is found in 10/268291 alleles at a frequency of 0.003% in the gnomAD v2.1.1 database, non-cancer dataset. The SpliceAI algorithm predicts no significant impact on splicing and the REVEL meta-predictor score (0.575) for this variant is indeterminate regarding the effect that it may have on protein function according to Pejaver 2022 thresholds (PMID: 36413997). To our knowledge, neither relevant clinical data nor well-established functional studies have been reported for this variant. This variant has been reported in hereditary cancer-suspected patients (PMID: 31921681, 30256826, 28528518) and has been assessed in case-control studies, where it has been found in both cases and controls, irrespective of the disease (PMID: 33471991, 31206626). This variant has been reported in the ClinVar database (1x likely benign, 13x uncertain significance) and has not been classified d in LOVD. Based on currently available information, the variant c.492T>G should be considered an uncertain significance variant according to ACMG/AMP classification guidelines. -
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:3Benign:1
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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]. -
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Fanconi anemia complementation group O Uncertain:3
This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 164 of the RAD51C protein (p.Phe164Leu). This variant is present in population databases (rs573992101, gnomAD 0.02%). This missense change has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 28528518, 35534704). ClinVar contains an entry for this variant (Variation ID: 188317). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt RAD51C 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. -
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
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not specified Uncertain:2
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Variant summary: RAD51C c.492T>G (p.Phe164Leu) results in a non-conservative amino acid change located in the ATP-binding domain (IPR020588) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-05 in 251476 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in RAD51C causing Hereditary Breast And Ovarian Cancer Syndrome (4e-05 vs 6.3e-05), allowing no conclusion about variant significance. c.492T>G, has been reported in the literature in individuals with personal and/or family history of breast and/or ovarian cancer, and other tumor phenotypes (e.g. Cock-Rada_2018, Martin-Morales_2018, Weitzel_2019, Oliver_2019), however it was also found in controls (e.g. Weitzel_2019 and in the FLOSSIES database). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. Co-occurrences with other pathogenic variant(s) have been reported (BRCA1 c.1674delA, p.Gly559ValfsX13). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28528518, 30256826, 31206626, 31921681, 33471991). ClinVar contains an entry for this variant (Variation ID: 188317). Based on the evidence outlined above, the variant was classified as uncertain significance. -
not provided Uncertain:2
The RAD51C c.492T>G (p.Phe164Leu) variant has been reported in the published literature in individuals with breast cancer (PMID: 28528518 (2017), 31206626 (2019), 35534704 (2022)) and colorectal cancer (PMID: 30256826 (2018)). In a large-scale breast cancer association study, this variant was observed in individuals with breast cancer as well as in reportedly healthy individuals (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/RAD51C)). The frequency of this variant in the general population, 0.00026 (9/34592 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. -
Observed in individuals meeting clinical criteria for Lynch syndrome or hereditary breast and ovarian cancer syndrome, as well as in both cases and controls in breast cancer studies (PMID: 28528518, 33471991, 30256826, 31921681, 31206626, 35534704, 37842866); 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: 30256826, 28528518, 31921681, 31206626, 14704354, 35534704, 33471991, 37842866, Vzquez2021) -
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at