NM_002878.4(RAD51D):c.715C>T (p.Arg239Trp) AND Breast-ovarian cancer, familial 4

Clinical significance:Uncertain significance (Last evaluated: Oct 28, 2020)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000409739.8

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]

Condition(s)

Name:
Breast-ovarian cancer, familial 4 (BROVCA4)
Synonyms:
BREAST-OVARIAN CANCER, FAMILIAL, SUSCEPTIBILITY TO, 4
Identifiers:
MONDO: MONDO:0013669; MedGen: C3280345; Orphanet: 145; OMIM: 614291

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000488994Counsylcriteria provided, single submitter
Uncertain significance
(Aug 2, 2016)
unknownclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Counsyl Autosomal Dominant Disease Classification criteria (2015),

Citation Link,

SCV000551328Invitaecriteria provided, single submitter
Uncertain significance
(Oct 28, 2020)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV000895089Fulgent Genetics,Fulgent Geneticscriteria provided, single submitter
Uncertain significance
(Oct 31, 2018)
unknownclinical testing

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

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedunknownunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Contribution of Germline Mutations in the RAD51B, RAD51C, and RAD51D Genes to Ovarian Cancer in the Population.

Song H, Dicks E, Ramus SJ, Tyrer JP, Intermaggio MP, Hayward J, Edlund CK, Conti D, Harrington P, Fraser L, Philpott S, Anderson C, Rosenthal A, Gentry-Maharaj A, Bowtell DD, Alsop K, Cicek MS, Cunningham JM, Fridley BL, Alsop J, Jimenez-Linan M, H√łgdall E, et al.

J Clin Oncol. 2015 Sep 10;33(26):2901-7. doi: 10.1200/JCO.2015.61.2408. Epub 2015 Aug 10.

PubMed [citation]
PMID:
26261251
PMCID:
PMC4554751

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
See all PubMed Citations (6)

Details of each submission

From Counsyl, SCV000488994.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1unknownunknownnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV000551328.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces arginine with tryptophan at codon 239 of the RAD51D protein (p.Arg239Trp). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and tryptophan. This variant is present in population databases (rs770250516, ExAC 0.004%). This variant has been observed in individuals and families affected with ovarian cancer (PMID: 22986143, 26261251, 24130102, 29409816). In both affected individuals and unaffected siblings, a pathogenic RAD51D variant c.694C>T (p.Arg232*) was also identified (PMID: 22986143, 24130102, 29409816). ClinVar contains an entry for this variant (Variation ID: 187225). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Benign; 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From Fulgent Genetics,Fulgent Genetics, SCV000895089.1

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

Last Updated: Oct 30, 2021

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