This germline variant was observed in a 58 year old woman with stage IIIC high-grade serous primary peritoneal carcinoma and was associated with tumor loss of the wild-type RAD51C allele. She had an exceptional response to cisplatin chemotherapy with no recurrence >10 years post diagnosis. This variant is very rare and is not reported in approximately 250K alleles on the gnomad database. In silico analyses predict this amino acid substitution to be damaging including PolyPhen2 and SIFT. This missense variant occurs in a highly conserved amino acid, which is the terminal amino acid in the functionally important Walker A nucleotide binding motif GXXXXGKT, predicting that it would impair RAD51C nucleotide binding and/or hydrolysis and hence HR function. Functional studies in the laboratory of Dr. Maria Jasin revealed defective complexing with RAD51 paralogs and defects in homologous recombination (Sullivan et al, 2021).
ClinVar Genomic variation as it relates to human health
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- Interpretation:
-
Likely pathogenic
- Review status:
- criteria provided, single submitter
- Submissions:
- 1
- First in ClinVar:
- Feb 20, 2021
- Most recent Submission:
- Feb 20, 2021
- Last evaluated:
- Jan 28, 2021
- Accession:
- VCV000996829.2
- Variation ID:
- 996829
- Description:
- single nucleotide variant
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NM_058216.3(RAD51C):c.394A>C (p.Thr132Pro)
- Allele ID
- 984544
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 17q22
- Genomic location
- 17: 58695179 (GRCh38) GRCh38 UCSC
- 17: 56772540 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_058216.3:c.394A>C MANE Select NP_478123.1:p.Thr132Pro missense NM_002876.4:c.394A>C NP_002867.1:p.Thr132Pro missense NR_103872.2:n.436A>C non-coding transcript variant NR_103873.1:n.362A>C non-coding transcript variant NC_000017.11:g.58695179A>C NC_000017.10:g.56772540A>C NG_023199.1:g.7578A>C NG_047169.1:g.1901T>G LRG_314:g.7578A>C - Protein change
- T132P
- Other names
- -
- Canonical SPDI
- NC_000017.11:58695178:A:C
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- dbSNP: rs2047959481
- VarSome
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Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Likely pathogenic | 1 | criteria provided, single submitter | Jan 28, 2021 | RCV001291630.2 |
Help
| Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation | Variation viewer | Related variants | ||
|---|---|---|---|---|---|---|
| HI score Help | TS score Help | Within gene | All | |||
| RAD51C | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh37 |
1649 | 1827 | |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Likely pathogenic
(Jan 28, 2021)
|
criteria provided, single submitter
Method: research
|
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Swisher Lab, University of Washington
Accession: SCV001478440.1
First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021 |
Comment:
This germline variant was observed in a 58 year old woman with stage IIIC high-grade serous primary peritoneal carcinoma and was associated with tumor loss … (more)
This germline variant was observed in a 58 year old woman with stage IIIC high-grade serous primary peritoneal carcinoma and was associated with tumor loss of the wild-type RAD51C allele. She had an exceptional response to cisplatin chemotherapy with no recurrence >10 years post diagnosis. This variant is very rare and is not reported in approximately 250K alleles on the gnomad database. In silico analyses predict this amino acid substitution to be damaging including PolyPhen2 and SIFT. This missense variant occurs in a highly conserved amino acid, which is the terminal amino acid in the functionally important Walker A nucleotide binding motif GXXXXGKT, predicting that it would impair RAD51C nucleotide binding and/or hydrolysis and hence HR function. Functional studies in the laboratory of Dr. Maria Jasin revealed defective complexing with RAD51 paralogs and defects in homologous recombination (Sullivan et al, 2021). (less)
Clinical Features:
Primary peritoneal carcinoma (present)
Age: 50-59 years
Sex: female
Testing laboratory: Swisher Lab
Date variant was reported to submitter: 2021-02-06
Testing laboratory interpretation: Likely pathogenic
|
Functional evidence
Help| There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Long-term survival of an ovarian cancer patient harboring a RAD51C missense mutation. | Sullivan MR | Cold Spring Harbor molecular case studies | 2021 | PMID: 33832919 |
Text-mined citations for rs2047959481...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
at this location. Please review the LitVar results carefully for your
variant of interest.
Record last updated Oct 08, 2022