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NM_002878.4(RAD51D):c.137C>G (p.Ser46Cys)

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Interpretation:
Conflicting interpretations of pathogenicity​

Likely benign(1);Uncertain significance(6)

Review status:
criteria provided, conflicting interpretations
Submissions:
8 (Most recent: Oct 22, 2021)
Last evaluated:
Oct 14, 2021
Accession:
VCV000127882.15
Variation ID:
127882
Description:
single nucleotide variant
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NM_002878.4(RAD51D):c.137C>G (p.Ser46Cys)

Allele ID
133339
Variant type
single nucleotide variant
Variant length
1 bp
Cytogenetic location
17q12
Genomic location
17: 35119118 (GRCh38) GRCh38 UCSC
17: 33446137 (GRCh37) GRCh37 UCSC
HGVS
Nucleotide Protein Molecular
consequence
NC_000017.10:g.33446137G>C
NM_002878.3:c.137C>G NP_002869.3:p.Ser46Cys missense
NC_000017.11:g.35119118G>C
... more HGVS
Protein change
S46C
Other names
p.S46C:TCT>TGT
Canonical SPDI
NC_000017.11:35119117:G:C
Functional consequence
-
Global minor allele frequency (GMAF)
-

Allele frequency
The Genome Aggregation Database (gnomAD) 0.00010
Trans-Omics for Precision Medicine (TOPMed) 0.00015
The Genome Aggregation Database (gnomAD), exomes 0.00008
Trans-Omics for Precision Medicine (TOPMed) 0.00012
Links
ClinGen: CA287956
dbSNP: rs587780102
VarSome
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Aggregate interpretations per condition

Interpreted condition Interpretation Number of submissions Review status Last evaluated Variation/condition record
Uncertain significance 2 criteria provided, multiple submitters, no conflicts Oct 22, 2020 RCV000228533.9
Uncertain significance 1 criteria provided, single submitter Nov 2, 2016 RCV000212953.6
Uncertain significance 1 criteria provided, single submitter Oct 14, 2021 RCV000656964.3
Uncertain significance 1 criteria provided, single submitter Jul 2, 2018 RCV000709453.1
Conflicting interpretations of pathogenicity 2 criteria provided, conflicting interpretations Aug 20, 2020 RCV000115808.12
Uncertain significance 1 no assertion criteria provided - RCV001354278.1
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Gene OMIM ClinGen Gene Dosage Sensitivity Curation Variation viewer Related variants
HI score Help TS score Help Within gene All
RAD51D Some evidence for dosage pathogenicity No evidence available GRCh38
GRCh37
11 1123
RAD51L3-RFFL - - - GRCh38 - 1105

Submitted interpretations and evidence

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Interpretation
(Last evaluated)
Review status
(Assertion criteria)
Condition
(Inheritance)
Submitter Supporting information
Uncertain significance
(Oct 14, 2021)
criteria provided, single submitter
Method: clinical testing
Not Provided
Allele origin: germline
GeneDx
Accession: SCV000149717.16
Submitted: (Oct 22, 2021)
Evidence details
Comment:
In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 22986143, 27616075, … (more)
Likely benign
(Aug 13, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Ambry Genetics
Accession: SCV000185614.6
Submitted: (Nov 30, 2020)
Evidence details
Publications
PubMed (3)
Comment:
In silico models in agreement (benign);No disease association in small case-control study
Uncertain significance
(Oct 22, 2020)
criteria provided, single submitter
Method: clinical testing
Breast-ovarian cancer, familial 4
Allele origin: germline
Invitae
Accession: SCV000287698.8
Submitted: (Jan 07, 2021)
Evidence details
Publications
PubMed (5)
Comment:
This sequence change replaces serine with cysteine at codon 46 of the RAD51D protein (p.Ser46Cys). The serine residue is highly conserved and there is a … (more)
Uncertain significance
(Nov 02, 2016)
criteria provided, single submitter
Method: clinical testing
not specified
Allele origin: germline
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV000604997.1
Submitted: (Jun 30, 2017)
Evidence details
Uncertain significance
(Mar 15, 2017)
criteria provided, single submitter
Method: clinical testing
Breast-ovarian cancer, familial 4
Allele origin: unknown
Counsyl
Accession: SCV000784997.2
Submitted: (Jun 20, 2018)
Evidence details
Publications
PubMed (4)
Uncertain significance
(Jul 02, 2018)
criteria provided, single submitter
Method: clinical testing
Hereditary breast and ovarian cancer syndrome
Allele origin: unknown
Mendelics
Accession: SCV000839197.1
Submitted: (Aug 20, 2018)
Evidence details
Uncertain significance
(Aug 20, 2020)
criteria provided, single submitter
Method: clinical testing
Hereditary cancer-predisposing syndrome
Allele origin: germline
Color Health, Inc
Accession: SCV000686419.4
Submitted: (Jun 11, 2021)
Evidence details
Comment:
This missense variant replaces serine with cysteine at codon 46 of the RAD51D protein. Computational prediction suggests that this variant may not impact protein structure … (more)
Uncertain significance
(-)
no assertion criteria provided
Method: clinical testing
Malignant tumor of breast
Allele origin: unknown
Department of Pathology and Laboratory Medicine,Sinai Health System
Additional submitter:
Franklin by Genoox
Study: The Canadian Open Genetics Repository (COGR)
Accession: SCV001548855.1
Submitted: (Mar 31, 2021)
Evidence details
Comment:
The RAD51D p.Ser46Cys variant was identified in 1 of 1172 proband chromosomes (frequency: 0.0009) from individuals or families with unselected ovarian cancer or at high … (more)

Functional evidence

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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

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Title Author Journal Year Link
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Nykamp K Genetics in medicine : official journal of the American College of Medical Genetics 2017 PMID: 28492532
Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Kobayashi Y Genome medicine 2017 PMID: 28166811
Gene panel sequencing in familial breast/ovarian cancer patients identifies multiple novel mutations also in genes others than BRCA1/2. Kraus C International journal of cancer 2017 PMID: 27616075
A germline homozygous mutation in the base-excision repair gene NTHL1 causes adenomatous polyposis and colorectal cancer. Weren RD Nature genetics 2015 PMID: 25938944
Loss of function germline mutations in RAD51D in women with ovarian carcinoma. Wickramanayake A Gynecologic oncology 2012 PMID: 22986143
Germline mutations in RAD51D confer susceptibility to ovarian cancer. Loveday C Nature genetics 2011 PMID: 21822267

Text-mined citations for rs587780102...

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These 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 Nov 27, 2021