chr17-58734199-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PVS1_Moderate
The NM_058216.3(RAD51C):c.1108C>T(p.Arg370Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000093 in 1,612,478 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R370R) has been classified as Likely benign.
Frequency
Consequence
NM_058216.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51C | NM_058216.3 | c.1108C>T | p.Arg370Ter | stop_gained | 9/9 | ENST00000337432.9 | |
LOC105371843 | XR_007065866.1 | n.81-9774G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51C | ENST00000337432.9 | c.1108C>T | p.Arg370Ter | stop_gained | 9/9 | 1 | NM_058216.3 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248636Hom.: 0 AF XY: 0.00000745 AC XY: 1AN XY: 134274
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1460370Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4AN XY: 726336
GnomAD4 genome AF: 0.0000526 AC: 8AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74296
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2022 | The p.R370* variant (also known as c.1108C>T) located in coding exon 9 of the RAD51C gene, results from a C to T substitution at nucleotide position 1108. This changes the amino acid from an arginine to a stop codon within coding exon 9. This alteration was detected in a cohort of 116 patients from Chinese familial breast cancer families (Dong L et al. Cancer Biol Med, 2021 Sep;19:850-70). This alteration occurs at the 3' terminus of the RAD51C gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last seven amino acids of the protein. The exact functional effect of this alteration is unknown. 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 | Jul 19, 2021 | This variant changes 1 nucleotide in exon 9 of the RAD51C gene, creating a premature translation stop signal in the last coding exon. While this mutant transcript is predicted to escape nonsense-mediated decay, it is expected to delete 7 amino acids from the C-terminus of the RAD51C protein. While to our knowledge, functional studies have not been reported for this variant, cells with a variant protein missing the 11 amino acids from the C-terminus have been reported to have reduced mitomycin C resistance (PMID: 12966089). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 4/280040 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 11, 2023 | Not observed at significant frequency in large population cohorts (gnomAD); Nonsense variant predicted to result in protein truncation as the last 4 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 12966089, 14704354, 37298034, 34570441, 32809180, 35171259) - |
Fanconi anemia complementation group O Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 23, 2024 | This sequence change creates a premature translational stop signal (p.Arg370*) in the RAD51C gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 7 amino acid(s) of the RAD51C protein. This variant is present in population databases (rs756744016, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with breast cancer (PMID: 32809180, 34570441). ClinVar contains an entry for this variant (Variation ID: 187300). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 | Dec 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at