17-58692677-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3
The NM_058216.3(RAD51C):c.34C>T(p.Arg12Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. 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. R12G) 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 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.34C>T | p.Arg12Trp | missense_variant | 1/9 | ENST00000337432.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.34C>T | p.Arg12Trp | missense_variant | 1/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251456Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461880Hom.: 1 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727240
GnomAD4 genome AF: 0.0000394 AC: 6AN: 152222Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74364
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 23, 2023 | The p.R12W variant (also known as c.34C>T), located in coding exon 1 of the RAD51C gene, results from a C to T substitution at nucleotide position 34. The arginine at codon 12 is replaced by tryptophan, an amino acid with dissimilar properties. This amino acid position is well 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 24, 2019 | - - |
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 07, 2022 | - - |
Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Nov 18, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | St. Jude Molecular Pathology, St. Jude Children's Research Hospital | Jun 10, 2021 | The RAD51C c.34C>T (p.Arg12Trp) missense change has a maximum subpopulation frequency of 0.0080% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/17-56770038-C-T?dataset=gnomad_r2_1). In silico tools are not in agreement about the effect of this variant on protein function, but to our knowledge these predictions have not been confirmed by functional assays. This variant is present 2X in the FLOSSIES database which contains genetic variants from women older than 70 years of age who have never had cancer (BS2_Supporting; https://whi.color.com/variant/17-56770038-C-T). This variant was investigated in a case control study of 81 patients with head and neck cancer and 156 healthy control individuals (PMID: 24631219) and a study of 132 breast cancer cases and 189 healthy control individuals (PMID: 31905201), however it was not observed in any cases or controls. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: BS2_Supporting. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 06, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies are inconclusive: moderately deficient homologous recombination activity and impaired protein-protein interactions (Prakash et al., 2022); This variant is associated with the following publications: (PMID: 24631219, 21537932, 36099300) - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 12 of the RAD51C protein (p.Arg12Trp). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with breast cancer (PMID: 21537932). ClinVar contains an entry for this variant (Variation ID: 409837). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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