chr17-58734187-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_058216.3(RAD51C):c.1096C>T(p.Arg366Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,612,968 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R366Q) 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 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.1096C>T | p.Arg366Trp | missense_variant | 9/9 | ENST00000337432.9 | |
LOC105371843 | XR_007065866.1 | n.81-9762G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.1096C>T | p.Arg366Trp | missense_variant | 9/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152100Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249630Hom.: 0 AF XY: 0.00000742 AC XY: 1AN XY: 134854
GnomAD4 exome AF: 0.00000958 AC: 14AN: 1460868Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 726616
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152100Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74310
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Aug 15, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 13, 2018 | Variant summary: RAD51C c.1096C>T (p.Arg366Trp) results in a non-conservative amino acid change in 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 3.2e-05 in 30974 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1096C>T, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Jonson_2016). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four 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. - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 01, 2022 | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in an individual with breast cancer (Jnson et al., 2016); This variant is associated with the following publications: (PMID: 22167183, 26740214, 14704354, 12966089) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 15, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jan 05, 2022 | This missense variant replaces arginine with tryptophan at codon 366 of the RAD51C 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 performed for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 26740214). In a large breast cancer case-control study, this variant has been observed in 0/60466 cases and 3/53458 controls (PMID: 33471991 - Leiden Open Variation Database DB-ID RAD51C_000075). This variant has been identified in 2/281028 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 19, 2022 | The p.R366W variant (also known as c.1096C>T), located in coding exon 9 of the RAD51C gene, results from a C to T substitution at nucleotide position 1096. The arginine at codon 366 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration has been reported in one Danish female diagnosed with breast cancer at age 34 and having a family history of prostate cancer and melanoma in first degree relatives (Jønson L et al. Breast Cancer Res. Treat. 2016 Jan;155:215-22). In one study, a different missense alteration at this same codon, (p.R366Q) was shown to partially segregate with disease in 1 family of a cohort of 480 families with breast and ovarian cancer, and was not identified in any of 620 families with breast cancer only, nor in 2912 healthy controls (Meindl A et al. Nat. Genet. 2010 May;42:410-4). In the same report, in vitro functional studies using p.R366Q mutant protein, demonstrated an intermediate defect of DNA repair activity in Rad51c-deficient DT40 chicken cells and little to no effect on localization to repair foci in response to DNA damaging agents in human RAD51D p.R366Q-mutated fibroblasts. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Fanconi anemia complementation group O;C3150659:Breast-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 03, 2021 | - - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 16, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 366 of the RAD51C protein (p.Arg366Trp). 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 and/or ovarian cancer (PMID: 26740214). ClinVar contains an entry for this variant (Variation ID: 142416). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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-ovarian cancer, familial, susceptibility to, 3 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at