NM_002878.4(RAD51D):c.715C>T (p.Arg239Trp) AND Hereditary cancer-predisposing syndrome

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(1) (Last evaluated: Sep 25, 2020)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
2 submissions [Details]
Record status:
current
Accession:
RCV000166936.5

Allele description [Variation Report for NM_002878.4(RAD51D):c.715C>T (p.Arg239Trp)]

NM_002878.4(RAD51D):c.715C>T (p.Arg239Trp)

Genes:
RAD51D:RAD51 paralog D [Gene - OMIM - HGNC]
RAD51L3-RFFL:RAD51L3-RFFL readthrough [Gene]
Variant type:
single nucleotide variant
Cytogenetic location:
17q12
Genomic location:
Preferred name:
NM_002878.4(RAD51D):c.715C>T (p.Arg239Trp)
HGVS:
  • NC_000017.11:g.35103277G>A
  • NG_031858.1:g.21593C>T
  • NM_001142571.2:c.775C>T
  • NM_002878.3:c.715C>T
  • NM_002878.4:c.715C>TMANE SELECT
  • NM_133629.3:c.379C>T
  • NP_001136043.1:p.Arg259Trp
  • NP_002869.3:p.Arg239Trp
  • NP_002869.3:p.Arg239Trp
  • NP_598332.1:p.Arg127Trp
  • LRG_516t1:c.715C>T
  • LRG_516:g.21593C>T
  • LRG_516p1:p.Arg239Trp
  • NC_000017.10:g.33430296G>A
  • NR_037711.2:n.741C>T
  • NR_037712.2:n.606C>T
  • NR_037714.1:n.467C>T
  • p.R239W
Protein change:
R127W
Links:
dbSNP: rs770250516
NCBI 1000 Genomes Browser:
rs770250516
Molecular consequence:
  • NM_001142571.2:c.775C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002878.3:c.715C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_002878.4:c.715C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_133629.3:c.379C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NR_037711.2:n.741C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_037712.2:n.606C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
  • NR_037714.1:n.467C>T - non-coding transcript variant - [Sequence Ontology: SO:0001619]
Observations:
1

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MedGen: C0027672

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000217755Ambry Geneticscriteria provided, single submitter
Uncertain significance
(Sep 25, 2020)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link,

SCV000902844Color Health, Inccriteria provided, single submitter
Likely benign
(Nov 13, 2015)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

Loss of function germline mutations in RAD51D in women with ovarian carcinoma.

Wickramanayake A, Bernier G, Pennil C, Casadei S, Agnew KJ, Stray SM, Mandell J, Garcia RL, Walsh T, King MC, Swisher EM.

Gynecol Oncol. 2012 Dec;127(3):552-5. doi: 10.1016/j.ygyno.2012.09.009. Epub 2012 Sep 14. Erratum in: Gynecol Oncol. 2014 Jan;132(1):260. Wickramanyake, Anneka [corrected to Wickramanayake, Anneka].

PubMed [citation]
PMID:
22986143
PMCID:
PMC3905744

About 1% of the breast and ovarian Spanish families testing negative for BRCA1 and BRCA2 are carriers of RAD51D pathogenic variants.

Gutiérrez-Enríquez S, Bonache S, de Garibay GR, Osorio A, Santamariña M, Ramón y Cajal T, Esteban-Cardeñosa E, Tenés A, Yanowsky K, Barroso A, Montalban G, Blanco A, Cornet M, Gadea N, Infante M, Caldés T, Díaz-Rubio E, Balmaña J, Lasa A, Vega A, Benítez J, de la Hoya M, et al.

Int J Cancer. 2014 May 1;134(9):2088-97.

PubMed [citation]
PMID:
24130102
See all PubMed Citations (5)

Details of each submission

From Ambry Genetics, SCV000217755.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

The p.R239W variant (also known as c.715C>T), located in coding exon 8 of the RAD51D gene, results from a C to T substitution at nucleotide position 715. The arginine at codon 239 is replaced by tryptophan, an amino acid with dissimilar properties. This alteration is reported to co-occur with the p.R232* (c.694C>T) pathogenic RAD51D mutation in a proband with ovarian cancer at age 43 (Wickramanyake A et al. Gynecol. Oncol. 2012 Dec;127:552-5). In another family, both alterations were found in a proband with ovarian cancer at age 44 and in four of her healthy siblings (Gutiérrez-Enríquez S et al. Int. J. Cancer. 2014 May;134:2088-97). Both of these alteration are also reported in a third family with two sisters with ovarian cancer at ages 47 and 46 and their three unaffected children (Sanchez-Bermudez AI et al. Eur J Med Genet. 2018 Jun;61(6):355-361). This variant was reported in 1/3429 patients with invasive epithelial ovarian cancer and 0/2772 controls (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7). 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

From Color Health, Inc, SCV000902844.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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